Substituted indazole derivatives active as kinase inhibitors

ABSTRACT

The present invention relates to substituted indazole compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by degulated protein kinase activity, like cancer. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such these compounds or the pharmaceutical compositions containing them.

The present invention relates to certain substituted indazole compounds,which modulate the activity of protein kinases. The compounds of thisinvention are therefore useful in treating diseases caused byderegulated protein kinase activity. The present invention also providesmethods for preparing these compounds, pharmaceutical compositionscomprising these compounds, and methods of treating diseases utilizingpharmaceutical compositions comprising these compounds.

The malfunctioning of protein kinases (PKs) is the hallmark of numerousdiseases. A large share of the oncogenes and proto-oncogenes involved inhuman cancers encode for PKs. The enhanced activities of PKs are alsoimplicated in many non-malignant diseases, such as benign prostatehyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis andpost-surgical stenosis and restenosis.

PKs are also implicated in inflammatory conditions and in themultiplication of viruses and parasites. PKs may also play a major rolein the pathogenesis and development of neurodegenerative disorders.

For a general reference to PKs malfunctioning or deregulation see, forinstance, Current Opinion in Chemical Biology (1999) 3, 459-465; Cell(2000) 100, 113-127; Nature Rev. Drug Discov. (2002) 1, 309-315; andCarcinogenesis (2008) 29, 1087-191.

A subset of PK is a group of membrane receptors with intrinsicprotein-tyrosine kinase activity (RPTK). Upon binding of growth factors,RPTKs become activated and phosphorylate themselves and a series ofsubstrates in the cytoplasm. Through this mechanism, they can transduceintracellular signallings for proliferation, differentiation or otherbiological changes. Structural abnormalities, over-expression andactivation of RTPKs are frequently observed in human tumors, suggestingthat constitutive ignition of the signal transduction leading to cellproliferation can result in malignant transformation.

FMS-like tyrosine kinase 3 (FLT3) and KIT are both members of the PDGFRfamily class III receptor tyrosine kinases characterized by anextracellular domain with 5 immunoglobulin-like loops, a transmembraneregion and a cytoplasmic domain containing not only the kinase domain(divided in two regions) but also an autoinhibitory juxtamembrane (JM)domain that docks with the kinase domain to stabilize a catalyticallyinactive conformation.

Normally, FLT3 has a crucial role in normal haematopoiesis and itsexpression is restricted to CD34+ hematopoietic stem/progenitor cells,brain, placenta, and gonads. Activation of FLT3 by FLT3-ligand promotesthe normal growth of early progenitor cells.

In acute leukemia, mutations of the FLT3 gene have been found to be oneof the most common acquired genetic lesions. FLT3 mutations can bedetected in 30% of acute myeloid leukemia (AML) patients (Nakao M, etal. Leukemia. 1996 December; 10(12): 1911-8), and also in 5-10% ofpatients with myelodisplastic syndrome (Horiike S, et al. Leukemia. 1997September; 11(9): 1442-6). There are two frequent types of somatic FLT3genetic mutations: internal tandem duplications (ITDs) in the JM domainand point mutations in the activation loop of the tyrosine kinase domain(TKD). ITD mutations are any elongation or shortening of the JM domainof FLT3 due to additions or deletions of amino acids that result in theconstitutive activation of FLT3. The presence of FLT3/ITD mutations isassociated with a poor clinical outcome in both pediatric and adultpatients with AML. Point mutations in the activation loop of the kinasedomain (FLT3/TKD) involve the aspartic acid, D835 residue, which leadsto an activated configuration and transformation of myeloid cells. D835mutations are missense mutations that result in substitution oftyrosine, histidine, valine, glutamic acid or asparagine for aspartaticacid at amino acid 835 of FLT3. These mutations have been reported in 7%of patients with AML. TKD mutations, unlike ITD mutations, have not beenshown to have any prognostic significance in AML patients. Both types ofFLT3 mutation cause ligand-independent activation of the receptor andactivation of downstream signalling pathways. Mutant FLT3 providessurvival advantage to leukemic cells because it causes activation ofthree major intracellular signalling pathways: PI3K/AKT; RAS/RAF/MAPKand JAK/STAT (Masson K, Rönnstrand L. Cell Signal. 2009 December;21(12): 1717-26).

In conclusion, interfering with the FLT3 signalling likely represents aspecific and effective way to block tumor cell proliferation in AML andpossibly other indications.

KIT is normally activated by stem cell factor. Signalling by KIT playsan important role in erythropoiesis, lymphopoiesis, mast celldevelopment and function, megakaryopoiesis, gametogenesis andmelanogenesis. Hematopoietic stem cells, multipotent progenitors andcommon myeloid progenitors, but also early T lineage progenitors andthymocytes express high levels of KIT. In addition, mast cells,melanocytes in the skin, and interstitial cells of Cajal in thedigestive tract express KIT (Pittoni P. et al. Oncogene 2011 Feb. 17;30(7): 757-69).

KIT overexpression or mutations can lead to cancer. Mutations in thisgene are frequently associated with gastrointestinal stromal tumors(GIST) (Antonescu C R. J Pathol. 2011; 223(2): 251-6). About 65-85% ofGISTs have KIT mutations, divided into two categories: mutations of thereceptor regulatory domains (extracellular and juxtamembrane) andmutation in the enzymatic domain. At diagnosis, the most frequentmutations, deletions and point mutations, affect JM domain.Extracellular domain mutations are the second most common mutationsfollowed by tyrosine kinase domain mutations. Mutation of KIT have beenidentified also in melanoma (Curtin J A, JCO, 2006, 24 (26): 4340-4346),acute myeloid leukemia (Malaise M, Steinbach D, Corbacioglu S, CurrHematol Malig Rep. 2009, 4(2): 77-82), and primary adenoid cysticcarcinoma of the salivary gland (Vila L, Liu H, Al-Quran S Z, Coco D P,Dong H J, Liu C, Mod Pathol. 2009; 22(10): 1296-302). Overexpression isreported also in thymic carcinoma (Ströbel P, Hohenberger P, Marx A, JThorac Oncol. 2010; 5 (10 Suppl 4): S286-90), glioma (Morris P G, AbreyL E. Target Oncol. 2010; 5(3):193-200), testicular seminoma (Nikolaou M.et al. Anticancer Res. 2007; 27(3B): 1685-8), and small cell lungcancers (SCLC) (Micke P, et al. Clin Cancer Res. 2003; 9(1): 188-94).Additional disorders are linked to KIT activation such as mast celldisease (Lim K H, Pardanani A, Tefferi A. Acta Haematol. 2008;119(4):194-8) or piebaldism (Murakami T, et al. J Dermatol Sci. 2004June; 35(1):29-33).

Based on the collection of data, KIT kinase activation appears to be thetriggering factor for an important group of malignancies, bothhematological and solid cancer diseases, thereby suggesting that itcould represent a good therapeutic target for the treatment of thesepathologies.

Several indazole derivatives useful for the therapy of a variety ofdiseases such as cancers, neurodegeneration and atherosclerosis havebeen disclosed in WO2003028720, WO2005085206, WO2008003396 andWO201069966 in the name respectively of Pharmacia Italia spa, HoffmannLa Roche AG, Merck GMBH and Nerviano Medical Sciences. Despite thesedevelopments, there is still a need for more effective agents.

We have now discovered that a series of indazoles are potent proteinkinase inhibitors and are thus useful in anticancer therapy.

Accordingly, a first object of the present invention is to provide asubstituted indazole compound represented by formula (I),

wherein:

Ar is a group selected from

wherein:

R1 is A, NR6R7, OR8, SO_(n)R9, COR10, nitro, cyano or an optionallysubstituted group selected from C₃-C₆ cycloalkyl, heterocyclyl andheteroaryl;

R2, R3, R4 and R5 are independently hydrogen, halogen, nitro, cyano,SO_(n)R9, COR10, NR11R12, OR13 or an optionally substituted groupselected from straight or branched C₁-C₆ alkyl, straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl andheterocyclyl wherein:

-   -   A is a straight or branched C₁-C₆ alkyl substituted with a group        selected from an optionally substituted heterocyclyl, an        optionally substituted heteroaryl, SO_(n)R9, COR10, NR11R12 and        OR13;    -   R6 is hydrogen or an optionally substituted group selected from        straight or branched C₁-C₆ alkyl, straight or branched C₂-C₆        alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,        heterocyclyl, aryl and heteroaryl;    -   R7 is hydrogen, SO_(n)R9, COR10, a substituted straight or        branched C₁-C₆ alkyl or an optionally substituted group selected        from straight or branched C₂-C₆ alkenyl, straight or branched        C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl and        heteroaryl or    -   R6 and R7, taken together with the nitrogen atom to which they        are bound, may form an optionally substituted heterocyclyl        group;    -   R8 is hydrogen, A, COR10 or an optionally substituted group        selected from straight or branched C₂-C₆ alkenyl, straight or        branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl and        heteroaryl, wherein A is as defined above;    -   R9 is NR11R12 or an optionally substituted group selected from        straight or branched C₁-C₆ alkyl, straight or branched C₂-C₆        alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,        heterocyclyl, aryl and heteroaryl;    -   R10 is hydrogen, NR11R12, OR13 or an optionally substituted        group selected from straight or branched C₁-C₆ alkyl, straight        or branched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl,        C₃-C₆ cycloalkyl, heterocyclyl, aryl and heteroaryl;    -   R11 and R12 are independently hydrogen, SO_(n)R9, COR10 or an        optionally substituted group selected from straight or branched        C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight or        branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl and        heteroaryl, wherein R9 and R10 are as defined above, or    -   R11 and R12, taken together with the nitrogen atom to which they        are bound, may form an optionally substituted heterocyclyl        group;    -   R13 is hydrogen, COR10 or an optionally substituted group        selected from straight or branched C₁-C₆ alkyl, straight or        branched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl,        C₃-C₆ cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R10        is as defined above;    -   n is 0, 1 or 2;

X is a bond or an optionally substituted group selected from straight orbranched C₁-C₆ alkyl, heterocycly and aryl;

Y is a bond, oxygen, or an optionally substituted group selected fromstraight or branched C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl,straight or branched C₂-C₆ alkynyl, heterocyclyl and aryl;

Z is a bond, oxygen or an optionally substituted straight or branchedC₁-C₆ alkyl;

Ar′ is an optionally substituted aryl or an optionally substitutedheteroaryl;

or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of synthesizing thesubstituted indazole derivatives of formula (I) prepared through aprocess consisting of standard synthetic transformations and isomers,tautomers, hydrates, solvates, complexes, metabolites, prodrugs,carriers, N-oxides.

The present invention also provides a method of treating diseases causedby and/or associated with deregulated protein kinase activity,particularly ABL, ACK1, AKT1, ALK, AUR1, AUR2, BRK, BUB1, CDC7/DBF4,CDK2/CYCA, CHK1, CK2, EEF2K, EGFR1, EphA2, EphB4, ERK2, FAK, FGFR1,FLT3, GSK3beta, Haspin, IGFR1, IKK2, IR, JAK1, JAK2, JAK3, KIT, LCK,LYN, MAPKAPK2, MELK, MET, MNK2, MPS1, MST4, NEK6, NIM1, P38alpha, PAK4,PDGFR, PDK1, PERK, PIM1, PIM2, PKAalpha, PKCbeta, PLK1, RET, ROS1,SULU1, Syk, TLK2, TRKA, TYK, VEGFR2, VEGFR3 or ZAP70 activity, moreparticularly FLT3, PDGFR, VEGFR3, TRKA or KIT activity, and further moreparticularly FLT3 or KIT activity, which comprises administering to amammal in need thereof an effective amount of a substituted indazolecompound represented by formula (I) as defined above.

A preferred method of the present invention is to treat a disease causedby and/or associated with deregulated protein kinase activity selectedfrom the group consisting of cancer, cell proliferation disorders andimmune cell-associated diseases and disorders.

Another preferred method of the present invention is to treat specifictypes of cancer selected from the group consisting of, but not limitedto, carcinoma such as bladder, breast, colon, kidney, liver, lung(including small cell lung cancer), salivary gland, esophagus,gall-bladder, ovary, pancreas, stomach, cervix, thyroid, thymus,prostate, and skin, including squamous cell carcinoma; hematopoietictumors of lymphoid lineage, including leukemia, acute lymphociticleukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma and Burkitt's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukemia; tumors ofmesenchymal origin, including gastrointestinal stromal tumor,fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheralnervous system, including astrocytoma neuroblastoma, glioma andschwannomas; other tumors, including mast cell disease, melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma andmesothelioma and others.

Another preferred method of the present invention is to treat specificcellular proliferation disorders such as, for example, benign prostatehyperplasia, familial adenomatosis polyposis, neurofibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis andpost-surgical stenosis and restenosis.

Another preferred method of the present invention is to treat immunecell-associated diseases and disorders, such as inflammatory andautoimmune diseases, for examples multiple sclerosis, systemic lupuserythematosis, inflammatory bowel diseases (IBD), Crohn's disease,irritable bowel syndrome, pancreatitis, ulcerative colitis,diverticulosis, myasthenia gravis, vasculitis, psoriasis, scleroderma,asthma, allergy, systemic sclerosis, vitiligo, arthritis such asosteoarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis.

Another preferred method of the present invention is to treat FLT3mutated cancers, such as acute myeloid leukemia or myelodisplasticsyndrome.

Another preferred method of the present invention is to treat KITmutated cancers, such as gastrointestinal stromal tumors, melanoma,acute myeloid leukemia, primary adenoid cystic carcinoma of the salivarygland, thymic carcinoma, glioma, testicular seminoma, small cell lungcancers, mast cell disease or piebaldism.

In addition, the method of the present invention also provides tumorangiogenesis and metastasis inhibition.

In a further preferred embodiment, the method of the present inventionfurther comprises subjecting the mammal in need thereof to a radiationtherapy or chemotherapy regimen in combination with at least onecytostatic or cytotoxic agent.

Moreover the invention provides an in vitro method for inhibiting FLT3or KIT protein kinase activity which comprises contacting the saidprotein with an effective amount of a compound of formula (I).

The present invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable excipient, carrier and/or diluent.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I) in combination with one or morechemotherapeutic—e.g. cytostatic or cytotoxic—agents, antibiotic-typeagents, alkylating agents, antimetabolite agents, hormonal agents,immunological agents, interferon-type agents, cyclooxygenase inhibitors(e.g. COX-2 inhibitors), matrixmetalloprotease inhibitors, telomeraseinhibitors, tyrosine kinase inhibitors, anti-growth factor receptoragents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents(e.g. angiogenesis inhibitors), farnesyl transferase inhibitors, ras-rafsignal transduction pathway inhibitors, cell cycle inhibitors, othercdks inhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like.

Additionally, the invention provides a product comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof, as definedabove, and one or more chemotherapeutic agents, as a combinedpreparation for simultaneous, separate or sequential use in anticancertherapy.

In yet another aspect the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof, as defined above, for useas a medicament.

Moreover, the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined above, for use in amethod of treating cancer.

Finally, the invention provides the use of a compound of formula (I) ora pharmaceutically acceptable salt thereof, as defined above, in themanufacture of a medicament with antitumor activity.

The compounds of formula (I) may have one or more asymmetric centres,and may therefore exist as individual optical isomers or racemicmixtures. Accordingly, all the possible isomers, and their mixtures, ofthe compounds of formula (I) are within the scope of the presentinvention.

In cases in which the compounds of formula (I) have unsaturatedcarbon-carbon double bonds, both the cis (Z) and trans (E) isomers arewithin the scope of this invention.

Derivatives of compounds of formula (I) originating from metabolism in amammal, and the pharmaceutically acceptable bio-precursors (otherwisereferred to as pro-drugs) of the compounds of formula (I) are alsowithin the scope of the present invention.

In addition to the above, as known to those skilled in the art, theunsubstituted nitrogen on the pyrazole ring of the compounds of formula(I) rapidly equilibrates in solution to form a mixture of tautomers, asdepicted below:

wherein Ar, Ar′, X, Y and Z are as defined above.

Accordingly, in the present invention, where only one tautomer isindicated for the compounds of formula (I), the other tautomer (Ia) isalso within the scope of the present invention, unless specificallynoted otherwise.

Moreover, if easily obtainable from the compounds of formula (I) asdefined above, also their hydrates, solvates, complexes and N-oxides arewithin the scope of the present invention.

N-oxides are compounds of formula (I) wherein nitrogen and oxygen aretethered through a dative bond.

The general terms as used herein, unless otherwise specified, have themeaning reported below.

The term “straight or branched C₁-C₆ alkyl” refers to a saturatedaliphatic hydrocarbon radical, including straight chain and branchedchain groups of from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl,2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. The alkylgroup may be substituted or unsubstituted; when not otherwise specified,the substituent groups are preferably one to three, independentlyselected from the group consisting of halogen, cyano, nitro, SO_(n)R9,COR10, NR11R12, OR13, R11R12N—(C₁-C₆)-alkyl, R13O—(C₁-C₆)-alkyl and anoptionally further substituted group selected from C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl and heteroaryl, whereinR9, R10, R11, R12, R13 and n are as defined above.

The term “C₃-C₆ cycloalkyl” refers to a 3- to 6-membered all-carbonmonocyclic ring, which may contain one or more double bonds but does nothave a completely conjugated π-electron system. Examples of cycloalkylgroups, without limitation, are cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl. Acycloalkyl group may be substituted or unsubstituted; when not otherwisespecified, the substituent groups are preferably one to three,independently selected from the group consisting of halogen, cyano,nitro, SO_(n)R9, COR10, NR11R12, OR13, R11R12N—(C₁-C₆)-alkyl,R13O—(C₁-C₆)-alkyl and an optionally further substituted straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, heterocyclyl, aryland heteroaryl, wherein R9, R10, R11, R12, R13 and n are as definedabove.

The term “heterocyclyl” refers to a 3- to 7-membered, saturated orpartially unsaturated carbocyclic ring where one or more carbon atomsare replaced by heteroatoms such as nitrogen, oxygen and sulfur. Notlimiting examples of heterocyclyl groups are, for instance, oxiranyl,aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperidinyl, pyrazolinyl, isoxazolidinyl, isoxazolinyl, thiazolidinyl,thiazolinyl, isothiazolinyl, dioxanyl, piperazinyl, morpholinyl,thiomorpholinyl, examethyleneiminyl, homopiperazinyl and the like. Aheterocyclyl group may be substituted or unsubstituted; when nototherwise specified, the substituent groups are preferably one to three,independently selected from the group consisting of halogen, cyano,nitro, SO_(n)R9, COR10, NR11R12, OR13, R11R12N—(C₁-C₆)-alkyl,R13O—(C₁-C₆)-alkyl and an optionally further substituted straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,heterocyclyl, aryl and heteroaryl, wherein R9, R10, R11, R12, R13 and nare as defined above.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic hydrocarbonwith from 1 to 4 ring systems, optionally further fused or linked toeach other by single bonds, wherein at least one of the carbocyclicrings is “aromatic”, wherein the term “aromatic” refers to completelyconjugated π-electron bond system. Non limiting examples of such arylgroups are phenyl, α- or β-naphthyl or biphenyl groups.

The term “heteroaryl” refers to aromatic heterocyclic rings, typically5- to 7-membered heterocycles with from 1 to 3 heteroatoms selectedamong N, O and S; the heteroaryl ring can be optionally further fused orlinked to aromatic and non-aromatic carbocyclic and heterocyclic rings.Not limiting examples of such heteroaryl groups are, for instance,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl,thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl,oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl,benzoimidazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl,1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl,2,3-dihydroquinoxalinyl and the like.

The aryl and heteroaryl groups may be substituted or unsubstituted; whennot otherwise specified, the substituent groups are preferably one tothree, independently selected from the group consisting of halogen,cyano, nitro, SO_(n)R9, COR10, NR11R12, OR13, R11R12N—(C₁-C₆)-alkyl,R13O—(C₁-C₆)-alkyl and an optionally further substituted straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,heterocyclyl, aryl and heteroaryl, wherein R9, R10, R11, R12, R13 and nare as defined above.

The term “halogen” indicates fluorine, chlorine, bromine or iodine.

The term “C₂-C₆ alkenyl” indicates an aliphatic C₂-C₆ hydrocarbon chaincontaining at least one carbon-carbon double bond and which can bestraight or branched. Representative examples include, but are notlimited to, ethenyl, 1-propenyl, 2-propenyl, 1- or 2-butenyl, and thelike.

The term “C₂-C₆ alkynyl” indicates an aliphatic C₂-C₆ hydrocarbon chaincontaining at least one carbon-carbon triple bond and which can bestraight or branched. Representative examples include, but are notlimited to, ethynyl, 1-propynyl, 2-propynyl, 1- or 2-butynyl, and thelike.

The alkenyl and alkynyl groups may be substituted or unsubstituted; whennot otherwise specified, the substituent groups are preferably one tothree, independently selected from the group consisting of halogen,cyano, nitro, SO_(n)R9, COR10, NR11R12, OR13, R11R12N—(C₁-C₆)-alkyl,R13O—(C₁-C₆)-alkyl and an optionally further substituted straight orbranched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl andheteroaryl, wherein R9, R10, R11, R12, R13 and n are as defined above.

The term “nitro” indicates a —NO₂ group.

The term “cyano” indicates a —CN residue.

The term “pharmaceutically acceptable salt” of compounds of formula (I)refers to those salts that retain the biological effectiveness andproperties of the parent compound. Such salts include acid additionsalts with inorganic acids such as hydrochloric, hydrobromic, nitric,phosphoric, sulfuric, perchloric acid and the like, or with organicacids such as acetic, trifluoroacetic, propionic, glycolic, lactic, (D)or (L) malic, maleic, fumaric, methanesulfonic, ethanesulfonic, benzoic,p-toluenesulfonic, salicylic, cinnamic, mandelic, tartaric, citric,succinic, malonic acid and the like; salts formed when an acidic protonpresent in a compound of formula (I) is either replaced by a metal ion,—e.g. an alkali metal ion such as sodium or potassium—or an alkalineearth ion, such as calcium or magnesium, or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

A preferred class of compounds of formula (I) are the compounds wherein:

R1 is A, NR6R7, OR8 or an optionally substituted heterocyclyl, whereinA, R6, R7 and R8 are as defined above.

A more preferred class of compounds of formula (I) are the compoundswherein:

Ar is Ar1 or Ar2; and R2, R3, R4, R5 are each independently hydrogen,halogen, NR11R12 or OR13, wherein R11, R12 and R13 are as defined above.

Specific compounds (Cpd.) of the invention or a salt thereof are listedbelow:

-   -   1.        N-(6-Benzyloxy-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide,    -   2.        4-(4-Methyl-piperazin-1-yl)-N-(6-phenoxy-1H-indazol-3-yl)-benzamide,    -   3.        N-[6-(3-Fluoro-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,    -   4.        N-[6-(4-Benzyloxy-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,    -   5.        4-(4-Methyl-piperazin-1-yl)-N-[6-(3-phenoxy-benzyloxy)-1H-indazol-3-yl]-benzamide,    -   6.        N-[6-(1-Benzyl-piperidin-4-yloxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,    -   7.        4-(4-Methyl-piperazin-1-yl)-N-[6-(3-phenyl-prop-2-ynyloxy)-1H-indazol-3-yl]-benzamide,    -   8.        4-(4-Methyl-piperazin-1-yl)-N-[6-(4-phenoxy-phenoxy)-1H-indazol-3-yl]-benzamide,    -   9.        N-[6-(3-Benzyloxy-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,    -   10.        4-(4-Methyl-piperazin-1-yl)-N-[6-(2-phenoxy-ethoxy)-1H-indazol-3-yl]-benzamide,    -   11.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,    -   12.        N-[6-(1-Benzyl-piperidin-3-yloxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,    -   13.        N-[6-(1-Benzyl-pyrrolidin-2-ylmethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,    -   14.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-4-oxy-piperazin-1-yl)-benzamide,    -   15.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-dimethylamino-piperidin-1-yl)-benzamide,    -   16.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-benzamide,    -   17.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide,    -   18.        4-{4-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-ylcarbamoyl]-phenyl}-piperazine-1-carboxylic        acid tert-butyl ester,    -   19.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-benzamide,    -   20.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-piperazin-1-yl-benzamide,    -   21.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-dimethylaminomethyl-benzamide,    -   22.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-benzamide,    -   23.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzamide,    -   24.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-morpholin-4-yl-benzamide,    -   25.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(2-morpholin-4-yl-ethylamino)-benzamide,    -   26.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(tetrahydro-pyran-4-ylamino)-benzamide,    -   27.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(1-methyl-piperidin-4-ylmethyl)-amino]-benzamide,    -   28.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(3-pyrrolidin-1-yl-azetidin-1-yl)-benzamide,    -   29.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-3-(4-methyl-piperazin-1-yl)-benzamide,    -   30.        N-{6-[2-(2-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,    -   31.        N-{6-[2-(3-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,    -   32.        N-{6-[2-(4-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,    -   33.        4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide,    -   34.        4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(3-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide,    -   35.        4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(pyridin-4-ylmethoxy)-ethoxy]-1H-indazol-3-yl}-benzamide,    -   36.        4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(pyridin-3-ylmethoxy)-ethoxy]-1H-indazol-3-yl}-benzamide,    -   37.        4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(pyridin-2-ylmethoxy)-ethoxy]-1H-indazol-3-yl}-benzamide,    -   38.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-2-fluoro-4-(4-methyl-piperazin-1-yl)-benzamide,    -   39.        4-(4-Methyl-piperazin-1-yl)-N-[6-((E)-3-phenyl-allyloxy)-1H-indazol-3-yl]-benzamide,    -   40.        N-{6-[2-(4-Methoxy-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,    -   41.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-1-oxy-piperidin-4-yl)-amino]-benzamide,    -   42.        4-(4-Methyl-4-oxy-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide        and    -   43.        N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-2,4-bis-(4-methyl-piperazin-1-yl)-benzamide.

The present invention also provides a process for the preparation of acompound of formula (I) as defined above, by using the reaction routesand synthetic schemes described below, employing the techniquesavailable in the art and starting materials readily available. Thepreparation of certain embodiments of the present invention is describedin the examples that follow, but those of ordinary skill in the art willrecognize that the preparations described may be readily adapted toprepare other embodiments of the present invention. For example, thesynthesis of non-exemplified compounds according to the invention may beperformed by modifications apparent to those skilled in the art, forinstance by appropriately protecting interfering groups, by changing toother suitable reagents known in the art, or by making routinemodifications of reaction conditions. Alternatively other reactionsreferred to herein or known in the art will be recognized as havingadaptability for preparing other compounds of the invention.

The reported Scheme 1 and Scheme 2 show the preparations of a compoundof formula (I).

wherein Ar is as defined in formula (I); W is hydroxy, halogen or asuitable leaving group; X, Y, Z and Ar′ are as defined in formula (I);and L is a suitable leaving group, such as halogen, methanesulfonyloxy,trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.

wherein Ar is as defined in formula (I); W is hydroxy, halogen or asuitable leaving group; X, Y, Z and Ar′ are as defined in formula (I);and L is a suitable leaving group, such as halogen, methanesulfonyloxy,trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.

All those with ordinary skills in the art will appreciate that anytransformation performed according to said methods may require standardmodifications such as, for instance, protection of interfering groups,change to other suitable reagents known in the art, or make routinemodifications of reaction conditions.

Accordingly, a process of the present invention comprises the followingsteps:

A) introducing the tert-butoxy-carbonyl group into the compound offormula (II)

B) cleaving the phthalimido group of the resultant compound of formula(III)

C) acylating the resultant compound of formula (IV)

by reaction with a compound of formula (V)

wherein Ar is as defined in formula (I) and W is hydroxy, halogen or asuitable leaving group;

D) selectively cleaving the tert-butyldimethylsilyl ether of theresultant compound of formula (VI)

wherein Ar is as defined in formula (I);

E) coupling the resultant compound of formula (VII)

wherein Ar is as defined in formula (I), alternatively with:

Ea) a compound of formula (VIII)

wherein Ar′, Z and Y are as defined in formula (I) and X is anoptionally substituted group selected from straight or branched C₁-C₆alkyl and heterocyclyl;

or

Eb) a compound of formula (IX)

wherein Ar′, Z and Y are as defined in formula (I) and X is anoptionally substituted aryl or

wherein Ar′ is as defined in formula (I) and X, Y and Z are a bond;

or

Ec) a compound of formula (X)

wherein Ar′, Z and Y are as defined in formula (I), X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl orheterocyclyl and L is a suitable leaving group, such as halogen,methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy;

F) cleaving the tert-butoxy-carbonyl group of the resultant compound offormula (XI) obtained in step Ea), Eb) or Ec)

wherein Ar, Ar′, X, Y and Z are as defined in formula (I), so as toobtain a compound of formula (I), as defined above; optionallyseparating the resultant compound of formula (I) into the singleisomers; optionally converting the resultant compound of formula (I)into a different compound of formula (I), and/or into a pharmaceuticallyacceptable salt if desired.

Alternatively, the intermediate compound of formula (XI), wherein Ar,Ar′, Y and Z are as defined in formula (I) and X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl andheterocyclyl, can be obtained in a process comprising the followingsteps:

G) selectively cleaving the tert-butyldimethylsilyl ether of thecompound of formula (IV), as defined above;

H) coupling the resultant compound of formula (XII)

alternatively with:

Ha) a compound of formula (VIII), as defined above;

or

Hb) a compound of formula (X), as defined above;

I) acylating the resultant compound of formula (XIII)

wherein Ar, Ar′, Y and Z are as defined in formula (I) and X is anoptionally substituted group selected from straight or branched C₁-C₆alkyl and heterocyclyl, with a compound of formula (V), as definedabove, so as to obtain a compound of formula (XI), wherein Ar, Ar′, Yand Z are as defined in formula (I) and X is an optionally substitutedgroup selected from straight or branched C₁-C₆ alkyl and heterocyclyl.

It is a further object of the present invention a process for preparingthe compound of formula (I), as defined above, comprising the followingsteps:

J) coupling the compound of formula (XIV)

alternatively with:

Ja) a compound of formula (VIII), as defined above;

or

Jb) a compound of formula (IX), as defined above;

or

Jc) a compound of formula (X), as defined above;

K) converting the resultant compound of formula (XV)

wherein Ar′, X, Y and Z are as defined in formula (I);

L) acylating the resultant compound of formula (XVI)

wherein Ar′, X, Y and Z are as defined in formula (I), with a compoundof formula (V), as defined above, so as to obtain a compound of formula(I), as defined above; optionally separating the resultant compound offormula (I) into the single isomers; optionally converting the resultantcompound of formula (I) into a different compound of formula (I), and/orinto a pharmaceutically acceptable salt if desired.

It is a further object of the present invention a process for preparinga compound of formula (I), wherein R1 is NR6R7, wherein R6 is as definedabove and R7 is hydrogen, a substituted straight or branched C₁-C₆ alkylor an optionally substituted group selected from straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,heterocyclyl, aryl and heteroaryl, and wherein Ar, Ar′, X, Y and Z areas defined above, comprising the following steps:

M) acylating the compound of formula (XVI), as defined above, with acompound of formula (XVII)

wherein R2, R3, R4 and R5 are as defined in formula (I) and W and L areas defined above;

N) coupling the resultant compound of formula (XVIII)

wherein Ar′, X, Y, Z, R2, R3, R4 and R5 are as defined in formula (I)and L is as defined above, with a compound of formula (XIX)

wherein R6 is as defined in formula (I) and R7 is hydrogen, asubstituted straight or branched C₁-C₆ alkyl or an optionallysubstituted group selected from straight or branched C₂-C₆ alkenyl,straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryland heteroaryl, so as to obtain a compound of formula (I), wherein R1 isNR6R7, wherein R6 is as defined in formula (I) and R7 is hydrogen, asubstituted straight or branched C₁-C₆ alkyl or an optionallysubstituted group selected from straight or branched C₂-C₆ alkenyl,straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryland heteroaryl, and Ar, Ar′, X, Y and Z are as defined in formula (I);optionally separating the resultant compound of formula (I) into thesingle isomers; optionally converting the resultant compound of formula(I) into a different compound of formula (I), and/or into apharmaceutically acceptable salt if desired.

As said above, the compounds of formula (I) which are prepared accordingto the process object of the invention, can be conveniently convertedinto other compounds of formula (I) by operating according to well-knownsynthetic conditions, the following being examples of possibleconversions:

1) reducing a compound of formula (I) wherein one of the substituentsR1, R2, R3, R4 or R5 is NO₂, for obtaining the corresponding compound offormula (I) wherein such substituent is NH₂;

2) acylating a compound of formula (I) wherein one of the substituentsR1, R2, R3, R4 or R5 is NH₂, by reaction with an acylating agent offormula (XX) or (XXI)

wherein R9, R10 and W are as defined above, for obtaining thecorresponding compound of formula (I) wherein such substituent is aNHSO₂R9 or NHCOR10 residue, wherein R9 and R10 are as defined above;

3) reacting a compound of formula (I) wherein the substituent R1 is NH₂,with a suitable aldehyde or ketone in the presence of a reducing agent,for obtaining the corresponding compound of formula (I) wherein suchsubstituent is a NR6R7 group, wherein R7 is hydrogen and R6 is asdefined in formula (I) except hydrogen;

4) reacting a compound of formula (I) wherein one of the substituentsR2, R3, R4 or R5 is NH₂, with a suitable aldehyde or ketone in thepresence of a reducing agent, for obtaining the corresponding compoundof formula (I) wherein such substituent is a NR11R12 group, wherein oneof the R11 or R12 is hydrogen and the other is as defined in formula (I)except hydrogen, SO_(n)R9 or COR10;

5) hydrolysing a compound of formula (I) wherein one of the substituentsR1, R2, R3, R4 or R5 is a COOR13 residue, wherein R13 is a straight orbranched C₁-C₆ alkyl, under acid or basic catalysis, so as to obtain thecorresponding compound of formula (I) wherein such substituent is a COOHgroup, in which case R13 represents hydrogen;

6) amidating a compound of formula (I) wherein one of the substituentsR1, R2, R3, R4 or R5 is a COOH residue, with an amine of formula (XXII)

wherein R11 and R12 are as defined in formula (I) except SO_(n)R9 orCOR10, for obtaining the corresponding compound of formula (I) whereinsuch substituent is a CONR11R12 residue, wherein R11 and R12 are asdefined in formula (I) except SO_(n)R9 or COR10;

7) oxidazing a compound of formula (I) wherein R1 is4-methyl-piperazin-1-yl for obtaining the corresponding compound offormula (I) wherein such substituent is 4-methyl-4-oxy-piperazin-1-yl;

8) cleaving the tert-butoxy-carbonyl group of a compound of formula (I)wherein R1 is 4-tert-butoxycarbonyl-piperazin-1-yl for obtaining thecorresponding compound of formula (I) wherein such substituent ispiperazin-1-yl.

According to step A), the transformation of the compound of formula (II)into the compound of formula (III) can be accomplished in a variety ofways and experimental conditions, which are widely known in the art forthe introduction of the tert-butoxy-carbonyl group, for example usingdi-tert-butyl dicarbonate. Preferably, this reaction is carried out in asuitable solvent such as, for instance, tetrahydrofuran,dichloromethane, toluene, 1,4-dioxane, and in the presence of a protonscavenger such as, for example, pyridine, triethylamine,N,N-diisopropylethylamine, at a temperature ranging from roomtemperature to reflux, for a time ranging from about 30 min. to about 96hours.

According to step B), the cleavage of the phthalimido group of thecompound of formula (III) to give the compound of formula (IV) can beaccomplished in a variety of ways and experimental conditions, which arewidely known in the art, for example using hydrazine. Preferably, thisreaction is carried out in a suitable solvent such as, for instance,tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane, at a temperatureranging from room temperature to reflux, for a time ranging from about30 min. to about 96 hours.

According to step C), a compound of formula (VI) can be obtained byreacting a compound of formula (IV) with a compound of formula (V) in avariety of ways and experimental conditions, which are widely known inthe art for acylation reactions. Preferably a compound of formula (V)wherein W is hydroxy is converted into its corresponding acyl chloridewherein W is chlorine in the presence of thionyl chloride or oxalylchloride, in a suitable solvent, such as toluene, dichloromethane,chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, or a mixturethereof, at a temperature ranging from about −10° C. to reflux and for aperiod of time varying from about 1 hour to about 96 hours. The acylchloride is isolated by evaporation of the solvent and further reactedwith (IV) in the presence of a base such as pyridine, triethylamine orN,N-diisopropylethylamine, at a temperature ranging from about −40° C.to reflux and for a period of time varying from about 1 hour to about 96hours. A suitable solvent may also be added, such as toluene,dichloromethane, chloroform, diethyl ether, tetrahydrofuran,1,4-dioxane. Alternatively, a compound of formula (IV) is reacted with acompound of formula (V) wherein W is hydroxy in the presence of anactivating agent such as hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropyl carbodiimide,1-ethyl-3-(3′-dimethylamino)carbodiimide hydrochloric acid salt,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Preferably, this reaction is carried out in a suitable solvent such as,for instance, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide and in the presence of aproton scavenger such as, for example, pyridine, triethylamine,N,N-diisopropylethylamine, at a temperature ranging from roomtemperature to reflux, for a time ranging from about 30 min. to about 96hours.

According to step D), the selective cleavage of thetert-butyldimethylsilyl ether of the compound of formula (VI) to givethe compound of formula (VII) can be carried out in a variety of ways,according to conventional methods well known in the literature.Preferably this conversion is carried out in the presence oftetrabutylammonium fluoride in a suitable solvent, such as, forinstance, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane, at atemperature ranging from −10° C. to reflux, for a time ranging fromabout 30 min. to about 96 hours.

According to step Ea), the coupling of a compound of formula (VII) withan alcohol of formula (VIII) to give a compound of formula (XI) can beaccomplished in a variety of ways and experimental conditions which arewidely known in the art for the synthesis of aryl ethers underMitsunobu-like conditions. Preferably this conversion is carried out inthe presence of an azodicarboxylate, such as, for example, diethylazodicarboxylate, diisopropyl azodicarboxylate or di-tert-butylazodicarboxylate and a phosphine, such as, for example,triphenylphosphine or polymer-bound triphenylphosphine, in a suitablesolvent, such as, for instance, tetrahydrofuran, dichloromethane,1,4-dioxane, toluene, acetonitrile at a temperature ranging from −20° C.to reflux, for a time ranging from about 30 min. to about 96 hours.

According to step Eb), the coupling of a compound of formula (VII) witha boronic acid of formula (IX) to give a compound of formula (XI) can beaccomplished in a variety of ways and experimental conditions which arewidely known in the art for the synthesis of di-aryl ethers. Preferablythis conversion is carried out in the presence of copper diacetate and4A molecular sieve or silica gel, in a suitable solvent, such as, forinstance, tetrahydrofuran, dichloromethane, 1,4-dioxane and in thepresence of a proton scavenger such as, for example, pyridine,triethylamine, N,N-diisopropylethylamine, at a temperature ranging from−10° C. to reflux, for a time ranging from about 30 min. to about 96hours.

According to step Ec), the coupling of a compound of formula (VII) witha compound of formula (X) to give a compound of formula (XI) can beaccomplished in a variety of ways and experimental conditions which arewidely known in the art for the alkylation of phenols. Preferably acompound of formula (VII) is treated with a chloride, bromide, iodide,mesylate or triflate of formula (X), in which case L representschlorine, bromine, iodine, methanesulfonyloxy ortrifluoromethanesulfonyloxy, respectively, in the presence of a protonscavenger such as, for example, triethylamine,N,N-diisopropylethylamine, sodium, potassium or cesium carbonate, in asuitable solvent such as, for instance, tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide, dimethoxyethane, at atemperature ranging from −10° C. to reflux, for a time ranging fromabout 30 min. to about 96 hours.

According to step F), the transformation of a compound of formula (XI)into a compound of formula (I) can be carried out in a variety of ways,according to conventional methods well known in the literature for thecleavage of a tert-butoxy-carbonyl group. As an example, this reactionmay be run under acidic conditions, for example in the presence of aninorganic or organic acid such as hydrochloric, trifluoroacetic ormethanesulfonic acid, in a suitable solvent such as dichloromethane,1,4-dioxane, a lower alcohol, such as methanol or ethanol, water, or amixture thereof, at a temperature ranging from room temperature toreflux and for a period of time ranging from about 30 min. to about 96hours.

According to step G), the transformation of the compound of formula (IV)into the compound of formula (XII) can be carried out in a way analogousto that specified above under D).

According to step Ha), the coupling between the compound of formula(XII) and an alcohol of formula (VIII) can be carried out in a wayanalogous to that specified above under Ea).

According to step Hb), the coupling between the compound of formula(XII) and a compound of formula (X) can be carried out in a wayanalogous to that specified above under Ec).

According to step I), the acylation of the compound of formula (XIII)with a compound of formula (V) can be carried out in a way analogous tothat specified above under C).

According to step Ja), the coupling between the compound of formula(XIV) and an alcohol of formula (VIII) can be carried out in a wayanalogous to that specified above under Ea).

According to step Jb), the coupling between the compound of formula(XIV) and a boronic acid of formula (IX) can be carried out in a wayanalogous to that specified above under Eb).

According to step Jc), the coupling between the compound of formula(XIV) and a compound of formula (X) can be carried out in a wayanalogous to that specified above under Ec).

According to step K), a compound of formula (XV) can be transformed intoa compound of formula (XVI) in a variety of ways and experimentalconditions. Preferably, this reaction is carried out in the presence ofhydrazine or hydrazine monohydrate in a suitable solvent such as, forinstance, toluene, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide,acetonitrile, methanol, ethanol or n-butanol, at a temperature rangingfrom 0° C. to reflux and for a period of time varying from about 30 minto about 96 hours.

According to step L), the acylation of the compound of formula (XVI)with a compound of formula (V) can be carried out in a way analogous tothat specified above under C).

According to step M), the acylation of the compound of formula (XVI)with a compound of formula (XVII) can be carried out in a way analogousto that specified above under C).

According to step N), the coupling of a compound of formula (XVIII) withan amine of formula (XIX) can be carried out in a variety of ways,according to conventional methods well known in the literature forBuchwald-Hartwig aminations. Preferably a compound of formula (XVIII)wherein L is chlorine, bromine, iodine or trifluoromethanesulfonyloxy isreacted with a compound of formula (XIX) in a suitable solvent such as,for example, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide,N,N-dimethylacetamide, dimethoxyethane, acetonitrile, toluene, in thepresence of catalytic amounts of a palladium derivative, such as, forexample, tris(dibenzylideneacetone)dipalladium(0), palladium diacetate,and a phosphine ligand, such as, for example,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, in the presenceof a base, such as, for instance, sodium or lithiumbis(trimethylsilyl)amide, sodium or potassium tert-butoxide, sodium,potassium or cesium carbonate, at a temperature ranging from 0° C. toreflux and for a period of time varying from about 15 min to about 96hours.

According to the conversion 1), the reduction of a compound of formula(I) wherein one of the substituents R1, R2, R3, R4 or R5 is nitro, forobtaining a compound of formula (I) wherein such substituent is amino,can be carried out in a variety of ways, according to conventionalmethods well known in the literature. Preferably this conversion iscarried out in a suitable solvent such as, for instance, methanol,ethanol, water, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide,acetic acid, or a mixture thereof, in the presence of a suitablereducing agent, such as, for instance, hydrogen and a hydrogenationcatalyst, or by treatment with cyclohexene or cyclohexadiene, or formicacid or ammonium formate and a hydrogenation catalyst, or a metal suchas iron or zinc in the presence of an inorganic acid, such ashydrochloric acid, or by treatment with tin (II) chloride or sodiumhydrosulfite in the presence of tetrabutylammonium chloride, at atemperature ranging from 0° C. to reflux and for a time varying fromabout 1 hour to about 96 hours. The hydrogenation catalyst is usually ametal, most often palladium, which can be used as such or supported oncarbon.

According to the conversion 2), the acylation of a compound of formula(I) wherein one of the substituents R1, R2, R3, R4 or R5 is NH₂, byreaction with an acylating agent of formula (XX) or (XXI) to give acompound of formula (I) wherein such substituent is a NHSO₂R9 or NHCOR10residue, can be carried out in a variety of ways, according toconventional methods well known in the literature. Preferably thisconversion is carried out in a way analogous to that specified aboveunder C).

According to the conversion 3), the reaction of a compound of formula(I), wherein the substituent R1 is NH₂, with a suitable aldehyde orketone for obtaining a compound of formula (I) wherein such substituentis a NR6R7 group, can be conducted in a variety of ways, according toconventional methods for carrying out reductive alkylations. Preferably,this reaction is carried out in a suitable solvent such as, forinstance, methanol, N,N-dimethylformamide, dichloromethane,tetrahydrofuran, or a mixture thereof, in the presence of a suitablereducing agent such as, for instance, sodium borohydride,tetra-alkylammonium borohydride, sodium cyano borohydride, sodiumtriacetoxyborohydride, tetramethylammonium triacetoxy borohydride and inthe presence of an acid catalyst, such as, for instance, acetic acid ortrifluoroacetic acid, at a temperature ranging from about 0° C. toreflux and for a time varying from about 1 hour to about 96 hours.

According to the conversion 4), the reaction of a compound of formula(I), wherein one of the substituents R2, R3, R4 or R5 is NH₂, with asuitable aldehyde or ketone in the presence of a reducing agent, forobtaining a compound of formula (I) wherein such substituent is aNR11R12 group, can be conducted in a variety of ways, according toconventional methods for carrying out reductive alkylations. Preferablythis conversion is carried out in a way analogous to that specifiedabove under 3).

According to the conversion 5), the hydrolysis of a compound of formula(I) wherein one of the substituents R1, R2, R3, R4 or R5 is a COOR13residue, wherein R13 is a straight or branched C₁-C₆ alkyl, to give thecorresponding carboxylic acid can be conducted in a variety of ways,according to methods widely known in the art for the hydrolysis of estergroups. Preferably such hydrolysis is carried out in the presence of aninorganic base, such as, for example, lithium, sodium or potassiumhydroxide, or an inorganic or organic acid, such as, for example,hydrochloric acid, trifluoroacetic acid, in a suitable solvent such as,for instance, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, water ora mixture thereof, at a temperature ranging from about 0° C. to refluxand for a time varying from about 1 hour to about 96 hours.

According to the conversion 6), the amidation of a compound of formula(I) wherein one of the substituents R1, R2, R3, R4 or R5 is a COOHresidue, with an amine of formula (XXII), can be can be conducted in avariety of ways, according to conventional methods for the synthesis ofcarboxamides. Preferably, this conversion is carried out in the presenceof an activating agent such as hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropyl carbodiimide,1-ethyl-3-(3′-dimethylamino)carbodiimide hydrochloric acid salt,O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, ina suitable solvent such as, for instance, tetrahydrofuran,dichloromethane, toluene, 1,4-dioxane, N,N-dimethylformamide,N,N-dimethylacetamide and in the presence of a proton scavenger such as,for example, pyridine, triethylamine, N,N-diisopropylethylamine, at atemperature ranging from room temperature to reflux, for a time rangingfrom about 30 min. to about 96 hours.

According to the conversion 7), the oxidation of a compound of formula(I) wherein R1 is 4-methyl-piperazin-1-yl for obtaining a compound offormula (I) wherein such substituent is 4-methyl-4-oxy-piperazin-1-ylcan be conducted in a variety of ways, according to conventional methodsfor the N-oxidation of tertiary amines. Preferably, this conversion iscarried out in the presence of an oxidizing agent such as, for example,3-chloroperbenzoic acid, hydrogen peroxide, dimethyldioxirane, in asuitable solvent such as, for instance, dichloromethane, methanol,ethanol, water, acetone, or a mixture thereof, at a temperature rangingfrom −10° C. to reflux, for a time ranging from about 30 min. to about96 hours.

According to the conversion 8) the cleavage of the tert-butoxy-carbonylgroup of a compound of formula (I) wherein R1 is4-tert-butoxycarbonyl-piperazin-1-yl for obtaining a compound of formula(I) wherein such substituent is piperazin-1-yl can be carried out in away analogous to that specified above under F).

It is known to the skilled person that when a compound of formula (V),formula (XVII), formula (XX) or formula (XXI) carries functional groupsthat may interfere in acylation reactions, such groups have to beprotected before carrying out the reaction. In particular, when acompound of formula (V), formula (XVII), formula (XX) or formula (XXI)is substituted by residues of general formula NR6R7, NR11R12, OR8, orOR13 wherein R8 or R13 or at least one of R6 and R7 or at least one ofR11 and R12 represent hydrogen, such groups may be protected as known inthe art. It is also known to the skilled person that such protectinggroup may be removed just after the reaction or at a later stage in thesynthetic process.

The deprotection of a compound of formula (I) wherein one of thesubstituents is a protected amino group can be made in a variety of waysaccording to conventional methods for deprotecting amino groups.Depending on the amino protecting group, this reaction can be conductedin different ways. In one aspect, such reaction can be carried out bytreatment with an inorganic acid, such as hydrochloric, sulphuric orperchloric acid, or an organic acid, such as trifluoroacetic ormethanesulfonic acid, in a suitable solvent, such as water, methanol,ethanol, 1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether,acetonitrile, N,N-dimethylformamide, dichloromethane or mixturesthereof, at a temperature ranging from −20° C. to 80° C., and for aperiod of time ranging from 30 minutes to 48 hours. In another aspect,such reaction can be carried out by treatment with an inorganic base,such as lithium or sodium or potassium hydroxide, or sodium or potassiumor cesium carbonate, or with an organic base, such as triethylamine orN,N-diisopropylethylamine, or with anhydrous hydrazine or hydrazinehydrate in a suitable solvent such as water, methanol, ethanol,1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether,acetonitrile, N,N-dimethylformamide, dichlorometane or mixtures thereof,at a temperature ranging from −20° C. to 80° C., and for a period oftime ranging from 30 minutes to 72 hours.

It is known to the skilled person that transformation of a chemicalfunction into another may require that one or more reactive centers inthe compound containing this function be protected in order to avoidundesired side reactions. Protection of such reactive centers, andsubsequent deprotection at the end of the synthetic transformations, canbe accomplished following standard procedures described, for instance,in: Green, Theodora W. and Wuts, Peter G. M.—Protective Groups inOrganic Synthesis, Third Edition, John Wiley & Sons Inc., New York(N.Y.), 1999.

In cases where a compound of formula (I) contains one or more asymmetriccenters, said compound can be separated into the single isomers byprocedures known to those skilled in the art. Such procedures comprisestandard chromatographic techniques, including chromatography using achiral stationary phase, or crystallization. General methods forseparation of compounds containing one or more asymmetric centers arereported, for instance, in Jacques, Jean; Collet, André; Wilen, SamuelH., —Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc.,New York (N.Y.), 1981.

A compound of formula (I) can also be transformed into apharmaceutically acceptable salt according to standard procedures thatare known to those skilled in the art. Alternatively, a compound offormula (I) that is obtained as a salt can be transformed into the freebase or the free acid according to standard procedures that are known tothe skilled person.

According to any variant of the process for preparing the compounds offormula (I), the starting materials and any other reactant, i.e.compounds of formula (II), (V), (VIII), (IX), (X), (XIV), (XVII), (XIX),(XX), (XXI) and (XXII) are either commercially available, known, oreasily prepared according to well-known methods described, for instance,in: B. M. Trost and I. Fleming, Comprehensive Organic Synthesis, 1991,Pergamon Press; A. R. Katritzky, O. Meth-Cohn and C. W. Rees,Comprehensive Organic Functional Group Transformations, 1995, ElsevierPergamon; A. R. Katritzky and R. J. K. Taylor, Comprehensive OrganicFunctional Group Transformations II, 2005, Elsevier Pergamon. Inparticular, the compound of formula (II) can be prepared as described inWO2003028720 and the compound of formula (XIV) is commerciallyavailable.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with cytostatic or cytotoxic agents, antibiotic-type agents,alkylating agents, antimetabolite agents, hormonal agents, immunologicalagents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors,tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HERagents, anti-EGFR agents, anti-angiogenesis agents (e.g. angiogenesisinhibitors), farnesyl transferase inhibitors, ras-raf signaltransduction pathway inhibitors, cell cycle inhibitors, other cdksinhibitors, tubulin binding agents, topoisomerase I inhibitors,topoisomerase II inhibitors, and the like.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) may be used sequentially with known anticanceragents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight,conditions of the patient and administration route.

For example, a suitable dosage adopted for oral administration of acompound of formula (I) may range from about 10 to about 1000 mg perdose, from 1 to 5 times daily. The compounds of the invention can beadministered in a variety of dosage forms, e.g., orally, in the formtablets, capsules, sugar or film coated tablets, liquid solutions orsuspensions; rectally in the form suppositories; parenterally, e.g.,intramuscularly, or through intravenous and/or intrathecal and/orintraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form. For example, the solidoral forms may contain, together with the active compound, diluents,e.g., lactose, dextrose saccharose, sucrose, cellulose, corn starch orpotato starch; lubricants, e.g., silica, talc, stearic acid, magnesiumor calcium stearate, and/or polyethylene glycols; binding agents, e.g.,starches, arabic gum, gelatine methylcellulose, carboxymethylcelluloseor polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates,laurylsulphates; and, in general, non-toxic and pharmacologicallyinactive substances used in pharmaceutical formulations. Thesepharmaceutical preparations may be manufactured in known manner, forexample, by means of mixing, granulating, tabletting, sugar-coating, orfilm-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions. As an example, the syrups may contain, ascarrier, saccharose or saccharose with glycerine and/or mannitol andsorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol. The suspension orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g., sterilewater, olive oil, ethyl oleate, glycols, e.g., propylene glycol and, ifdesired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

With the aim of better illustrating the present invention, withoutposing any limitation to it, the following examples are now given.

EXPERIMENTAL SECTION

For a reference to any specific compound of formula (I) of theinvention, optionally in the form of a pharmaceutically acceptable salt,see the experimental section and claims. Referring to the examples thatfollow, compounds of the present invention were synthesized using themethods described herein, or other methods, which are well known in theart.

In the examples below, the short forms and abbreviations used hereinhave the following meaning.

ABBREVIATIONS EtOAc Ethyl acetate DCM Dichloromethane DIPEAN,N-Diisopropylethylamine DMF N,N-dimethylformamide DMSO Dimethylsulfoxide Et₂O Diethyl ether EtOH Ethanol HCl Hydrochloric acid K₂CO₃Potassium carbonate LiHMDS Lithium bis(trimethylsilyl)amide MeOHMethanol NaHCO₃ Sodium hydrogencarbonate NaOH Sodium hydroxide Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium(0) SOCl₂ Thionyl chloride TBAFTetra-n-butylammonium fluoride TEA Triethylamine TFA Trifluoroaceticacid THF Tetrahydrofurane g Gram mg Milligram ml Milliliter μlMicroliter M Molar mM Millimolar μM Micromolar N Normal mol Mole mmolMillimole h Hour min Minute r.t. Room temperature Hz Hertz MHzMega-Hertz CV Column volume HRMS High Resolution Mass Spectra ESIElectrospray ionization HPLC High-performance liquid chromatography

With the aim at better illustrating the present invention, withoutposing any limitation to it, the following examples are now given.

As used herein the symbols and conventions used in the processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry.

Unless otherwise noted, all materials were obtained from commercialsuppliers, of the best grade and used without further purification.Anhydrous solvent such as DMF, THF, DCM and toluene were obtained fromthe Aldrich Chemical Company. All reactions involving air- ormoisture-sensitive compounds were performed under nitrogen or argonatmosphere.

General Purification and Analytical Methods

Thin-layer chromatography (TLC) was performed on Merck silica gel 60F₂₅₄ pre-coated plates. Column chromatography was conducted either undermedium pressure on silica (Merck silica gel 40-63 μm) or performed byusing a Biotage SP1 Flash Purification system with prepacked silica gelcartridges (Biotage or Varian).

¹H-NMR spectra were recorded in DMSO-d₆ or CDCl₃ at a constanttemperature of 28° C. on a Varian INOVA 400 spectrometer operating at400.50 MHz and equipped with a 5 mm z-axis PFG Indirect Detection Probe(¹H{¹⁵N—³¹P}) and on a Varian Inova 500 spectrometer operating at 499.75MHz. Residual solvent signal was used as reference (δ=2.50 or 7.27 ppm).Chemical shifts (δ) are reported in parts per million (ppm) and couplingconstants (J) in Hz. The following abbreviations are used formultiplicities: s=singlet; bs=broad signal; d=doublet; t=triplet;m=multiplet; dd=doublet of doublets.

Electrospray (ESI) mass spectra were obtained on a Finnigan LCQ iontrap. Unless otherwise specified, all final compounds were homogeneous(purity of not less than 95%), as determined by high-performance liquidchromatography (HPLC). HPLC-UV-MS analyses, used to assess compoundpurity, were carried out combining the ion trap MS instrument with HPLCsystem SSP4000 (Thermo Separation Products) equipped with an autosamplerLC Pal (CTC Analytics) and UV6000LP diode array detector (UV detection215-400 nm). Instrument control, data acquisition and processing wereperformed with the Xcalibur 1.2 software (Finnigan). HPLC chromatographywas run at r.t., and 1 mL/min flow rate, using a Waters×Terra RP 18column (4.6×50 mm; 3.5 μm). Mobile phase A was ammonium acetate 5 mMbuffer (pH 5.5 with acetic acid): acetonitrile 90:10, and mobile phase Bwas ammonium acetate 5 mM buffer (pH 5.5 with acetic acid): acetonitrile10:90; the gradient was from 0 to 100% B in 7 minutes then hold 100% Bfor 2 minutes before requilibration.

ESI(+) high resolution mass spectra (HRMS) were obtained on a WatersQ-Tof Ultima directly connected with micro HPLC 1100 Agilent aspreviously described (Colombo, M.; Riccardi-Sirtori, F.; Rizzo, V.; Afully automated method for accurate mass determination usinghigh-performance liquid chromatography with a quadrupole/orthogonalacceleration time-of-flight mass spectrometer. Rapid Commun. MassSpectrom. 2004, 18, 511-517).

Preparation 16-(tert-butyl-dimethyl-silanyloxy)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-indazole-1-carboxylicacid tert-butyl ester (III)

Scheme 1, Step A)

A solution of2-[6-(tert-butyl-dimethyl-silanyloxy)-1H-indazol-3-yl]-isoindole-1,3-dione(786 mg, 2 mmol) in dry THF (10 ml) and DIPEA (1.4 ml, 8 mmol), underargon atmosphere, was treated with di-tert-butyl dicarbonate (495 mg,2.2 mmol) and stirred at r.t. overnight. The solvent was evaporatedunder reduced pressure and the crude residue purified by flashchromatography over silica gel eluting with hexane/EtOAc 7:3 affording884 mg (yield: 89%) of the title compound as a white solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 8.09-8.04 (m, 2H), 8.02-7.96 (m,2H), 7.77 (d, J=8.29 Hz, 1H), 7.55 (d, J=1.95 Hz, 1H), 7.00 (dd, J=2.07,8.78 Hz, 1H), 1.69 (s, 9H), 1.01 (s, 9H), 0.28 (s, 6H)

ESI (+) MS m/z 494 (MH⁺)

Preparation 23-Amino-6-(tert-butyl-dimethyl-silanyloxy)-indazole-1-carboxylic acidtert-butyl ester (IV)

Scheme 1, Step B)

A solution of6-(tert-butyl-dimethyl-silanyloxy)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-indazole-1-carboxylicacid tert-butyl ester (1.17 g, 2.37 mmol) in dry THF (20 ml), underargon atmosphere, was treated with 3.56 ml of 1M hydrazine in THF (3.56mmol). The mixture was stirred at reflux for 1 h then more 1M hydrazinein THF was added (8 ml). After stirring for additional 2 h at reflux,the reaction mixture was cooled to r.t. and the precipitated solidfiltered and washed with THF. The filtrate was evaporated to dryness andthe residue purified by flash chromatography over silica gel elutingwith DCM/acetone 7:3 affording 785 mg (yield: 91%) of the title compoundas a yellowish solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.71 (d, J=8.90 Hz, 1H), 7.37 (bs,1H), 6.81 (dd, J=2.07, 8.54 Hz, 1H), 6.21 (bs, 2H), 1.59 (s, 9H), 0.99(s, 9H), 0.23 (s, 6H)

ESI (+) MS m/z 364 (MH⁺)

Preparation 36-(tert-Butyl-dimethyl-silanyloxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

Scheme 1, Step C)

To a suspension of 4-(4-methyl-piperazin-1-yl)-benzoic acid (1.64 g,7.48 mmol) in dry THF (50 ml), under argon atmosphere, at r.t., wasadded thionyl chloride (1.37 ml, 18.9 mmol) and 3 drops of dry DMF. Thereaction mixture was heated to 50° C. and stirred for 5 h then thevolatiles were removed under reduced pressure. The residue was taken upin dry toluene (50 ml), re-evaporated and the solid residue dried underhigh vacuum. The resultant crude 4-(4-methyl-piperazin-1-yl)-benzoylchloride hydrochloride was suspended in 20 ml of dry THF and treateddropwise at r.t., under argon atmosphere, with a solution of3-amino-6-(tert-butyl-dimethyl-silanyloxy)-indazole-1-carboxylic acidtert-butyl ester (1.81 g, 4.98 mmol) in 20 ml of dry THF and 2.56 ml ofDIPEA (14.96 mmol). The reaction mixture was heated to 50° C. andstirred for 22 h. The volatiles were removed under reduced pressure, theresidue diluted with DCM (100 ml) and washed with a saturated solutionof NaHCO₃ (75 ml). The organic layer was separated, dried over sodiumsulfate and evaporated to dryness. The crude residue was purified byflash chromatography over silica gel eluting with DCM/MeOH/30% NH₃95:5:0.5 affording 1.88 g (yield: 67%) of the title compound.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.95 (s, 1H), 8.03-7.96 (m, 2H),7.73 (d, J=9.15 Hz, 1H), 7.51 (d, J=2.07 Hz, 1H), 7.06-7.01 (m, 2H),6.90 (dd, J=2.19, 8.78 Hz, 1H), 3.34-3.32 (m, 4H), 2.53-2.50 (m, 4H),2.27 (s, 3H), 1.65 (s, 9H), 1.00 (s, 9H), 0.27 (s, 6H)

ESI (+) MS m/z 566 (MH⁺)

Preparation 46-Hydroxy-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

Scheme 1, Step D)

A solution of6-(tert-butyl-dimethyl-silanyloxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester 1.88 g (3.33 mmol) in dry THF (20 ml) was treatedwith 1M TBAF in THF (4 ml, 4 mmol) and stirred at r.t. for 30 min. Water(20 ml) was then added and the mixture extracted with EtOAc (100 ml).The separated organic layer was dried over sodium sulfate and evaporatedto dryness. The residue was purified by flash chromatography over silicagel eluting with DCM/MeOH/30% NH₃ 92:8:0.8 affording, after triturationwith Et₂O, 1.5 g (yield: 100%) of the title compound.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.86 (s, 1H), 10.16 (s, 1H),8.02-7.94 (m, 2H), 7.65 (d, J=8.78 Hz, 1H), 7.48 (d, J=1.95 Hz, 1H),7.05-7.00 (m, 2H), 6.82 (dd, J=2.07, 8.78 Hz, 1H), 3.34-3.32 (m, 4H),2.55-2.45 (m, 4H), 2.27 (s, 3H), 1.65 (s, 9H)

ESI (+) MS m/z 452 (MH⁺)

Preparation 53-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-6-(3-phenoxy-benzyloxy)-indazole-1-carboxylicacid tert-butyl ester

Scheme 1, Step Ea)

A solution of triphenylphosphine (209 mg, 0.798 mmol) and diisopropylazodicarboxylate (0.152 ml, 0.732 mmol) in dry DCM (2 ml) was stirredunder argon at 4° C. for 15 min. The resultant mixture was then added toa stirred solution of6-hydroxy-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester (100 mg, 0.222 mmol) and(3-phenoxy-phenyl)-methanol (149 mg, 0.732 mmol) in 2 ml of dry DCM, atr.t., under argon. After stirring at r.t. overnight the reaction mixturewas adsorbed onto silica gel, dried, loaded into a silica gelchromatographic column and eluted with DCM/MeOH/30% NH₃ 95:5:0.5affording 87 mg (yield: 62%) of the title compound.

ESI (+) MS m/z 634 (MH⁺)

Operating in an analogous way, the following compounds were obtained:

6-Benzyloxy-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 542 (MH⁺)

3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-6-(3-phenyl-prop-2-ynyloxy)-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 566 (MH⁺)

6-(1-Benzyl-piperidin-4-yloxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 625 (MH⁺)

3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-6-(2-phenoxy-ethoxy)-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 572 (MH⁺)

6-(1-Benzyl-piperidin-3-yloxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 625 (MH⁺)

6-(1-Benzyl-pyrrolidin-2-ylmethoxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 625 (MH⁺)

Preparation 63-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-6-phenoxy-indazole-1-carboxylicacid tert-butyl ester

Scheme 1, Step Eb)

A mixture of6-hydroxy-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester (110 mg, 0.244 mmol), phenylboronic acid (92 mg,0.732 mmol), copper diacetate (45 mg, 0.244 mmol) and 4A molecularsieves (200 mg) in 5 ml of DCM was treated with TEA (0.339 ml, 2.44mmol). After stirring at r.t. for 2 days the solvent was removed underreduced pressure, the residue treated with DCM/MeOH/30% NH₃ 95:5:0.5,filtered and the filtrate loaded into a silica gel chromatographiccolumn and eluted with DCM/MeOH/30% NH₃ 95:5:0.5 affording 88 mg (yield:68%) of the title compound.

ESI (+) MS m/z 528 (MH⁺)

Operating in an analogous way, the following compounds were obtained:

6-(3-Fluoro-phenoxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 546 (MH⁺)

6-(4-Benzyloxy-phenoxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 634 (MH⁺)

3-[4-(4-Methyl-piperazin-1-yl)-benzoylamino]-6-(4-phenoxy-phenoxy)-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 620 (MH⁺)

6-(3-Benzyloxy-phenoxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

ESI (+) MS m/z 634 (MH⁺)

Preparation 7 3-Amino-6-hydroxy-indazole-1-carboxylic acid tert-butylester (XII)

Scheme 1, Step G)

A solution of3-amino-6-(tert-butyl-dimethyl-silanyloxy)-indazole-1-carboxylic acidtert-butyl ester 672 mg (1.85 mmol) in dry THF (10 ml) was treated with1M TBAF in THF (1.85 ml, 1.85 mmol) and stirred at r.t. for 30 min.Water (20 ml) was then added and the mixture extracted with EtOAc (3×50ml). The separated organic layers were combined, dried over sodiumsulfate and evaporated to dryness. The residue was purified by flashchromatography over silica gel eluting with DCM/EtOAc 6:4 affording 429mg (yield: 93%) of the title compound.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 9.93 (s, 1H), 7.60 (d, J=8.54 Hz,1H), 7.35 (bs, 1H), 6.71 (dd, J=2.19, 8.54 Hz, 1H), 6.10 (bs, 2H), 1.58(s, 9H)

ESI (+) MS m/z 250 (MH⁺)

Preparation 8 3-Amino-6-(2-benzyloxy-ethoxy)-indazole-1-carboxylic acidtert-butyl ester

Scheme 1, Step Hb)

A mixture of 3-amino-6-hydroxy-indazole-1-carboxylic acid tert-butylester (249 mg, 1 mmol), K₂CO₃ (152 mg, 1.1 mmol) and benzyl 2-bromoethylether (0.179 ml, 1.1 mmol) in dry DMF (5 ml) was stirred at 50° C. for12 h. More benzyl 2-bromoethyl ether (30 μl) was added and the mixturestirred at 50° C. for additional 4 h. The reaction mixture was pouredinto water (50 ml) and extracted with EtOAc (50 ml). The organic layerwad dried over sodium sulfate and evaporated to dryness. The cruderesidue was purified by flash chromatography over silica gel elutingwith DCM/EtOAc 7:3 affording 274 mg (yield: 72%) of the title compound.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.71 (d, J=8.66 Hz, 1H), 7.48 (bs,1H), 7.38-7.27 (m, 5H), 6.91 (dd, J=2.19, 8.66 Hz, 1H), 6.19 (bs, 2H),4.59 (s, 2H), 4.25-4.20 (m, 2H), 3.85-3.80 (m, 2H), 1.58 (s, 9H)

ESI (+) MS m/z 384 (MH⁺)

Preparation 96-(2-Benzyloxy-ethoxy)-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-indazole-1-carboxylicacid tert-butyl ester

Scheme 1, Step I)

A mixture of 4-(4-methyl-piperazin-1-yl)-benzoyl chloride hydrochloride,prepared from 248 mg (1.13 mmol) of 4-(4-methyl-piperazin-1-yl)-benzoicacid as described above in preparation 3, and DIPEA (0.386 ml, 2.25mmol) in dry THF (10 ml) was treated dropwise at r.t., under argonatmosphere, with a solution of3-amino-6-(2-benzyloxy-ethoxy)-indazole-1-carboxylic acid tert-butylester (143 mg, 0.374 mmol) in 10 ml of dry THF. The reaction mixture washeated up to 50° C. and stirred for 12 h. The volatiles were removedunder reduced pressure, the residue taken up in DCM (100 ml) and washedwith a saturated solution of NaHCO₃ (75 ml). The organic layer wasseparated, dried over sodium sulfate and evaporated to dryness and thecrude residue purified by flash chromatography over silica gel elutingwith DCM/MeOH 98:2 then 90:10 affording 124 mg (yield: 57%) of the titlecompound as a white solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.94 (s, 1H), 8.02-7.96 (m, 2H),7.75 (d, J=8.90 Hz, 1H), 7.61 (d, J=2.19 Hz, 1H), 7.39-7.27 (m, 5H),7.06-7.01 (m, 2H), 7.00 (dd, J=2.19, 8.90 Hz, 1H), 4.60 (s, 2H),4.31-4.25 (m, 2H), 3.88-3.83 (m, 2H), 3.34-3.32 (m, 4H), 2.53-2.46 (m,4H), 2.27 (s, 3H), 1.66 (s, 9H)

ESI (+) MS m/z 586 (MH⁺)

EXAMPLE 14-(4-Methyl-piperazin-1-yl)-N-[6-(3-phenoxy-benzyloxy)-1H-indazol-3-yl]-benzamide(Cpd. 5)

Scheme 1, Step F)

A solution of3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-6-(3-phenoxy-benzyloxy)-indazole-1-carboxylicacid tert-butyl ester (87 mg, 0.137 mmol) in DCM/TFA 8:2 (5 ml) wasstirred at r.t. for 2 h. The volatiles were removed under reducedpressure and the residue purified by flash chromatography over silicagel eluting with DCM/MeOH/30% NH₃ 90:10:1 affording 71 mg (yield: 97%)of the title compound as a white solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.46 (s, 1H) 10.38 (s, 1H) 7.94 (d,J=8.97 Hz, 2H) 7.59 (d, J=8.79 Hz, 1H) 7.30-7.43 (m, 3H) 7.25 (d, J=7.69Hz, 1H) 7.07-7.17 (m, 2H) 6.97-7.04 (m, 4H) 6.95 (dd, J=8.06, 1.83 Hz,1H) 6.90 (d, J=2.01 Hz, 1H) 6.75 (dd, J=8.88, 2.11 Hz, 1H) 5.18 (s, 2H)3.25-3.32 (m, 4H) 2.42-2.48 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 534 (MH⁺)

ESI (+) HRMS calcd for C₃₂H₃₁N₅O₃+H⁺: 534.2500; found 534.2488

Operating in an analogous way, the following compounds were obtained:

N-(6-Benzyloxy-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 1)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.46 (s, 1H), 10.40 (s, 1H),8.00-7.94 (m, 2H), 7.62 (d, J=9.02 Hz, 1H), 7.53-7.32 (m, 5H), 7.05-7.00(m, 2H), 6.93 (d, J=1.83 Hz, 1H), 6.78 (dd, J=2.19, 8.90 Hz, 1H), 5.20(s, 2H), 3.34-3.32 (m, 4H), 2.53-2.46 (m, 4H), 2.28 (s, 3H)

ESI (+) MS m/z 442 (MH⁺)

ESI (+) HRMS calcd for C₂₆H₂₇N₅O₂+H⁺: 442.2238; found 442.2237

4-(4-Methyl-piperazin-1-yl)-N-[6-(3-phenyl-prop-2-ynyloxy)-1H-indazol-3-yl]-benzamide(Cpd. 7)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53 (s, 1H), 10.42 (s, 1H),8.00-7.95 (m, 2H), 7.64 (d, J=8.90 Hz, 1H), 7.50-7.37 (m, 5H), 7.06-7.00(m, 3H), 6.78 (dd, J=2.19, 9.02 Hz, 1H), 5.13 (s, 2H), 3.34-3.32 (m,4H), 2.53-2.46 (m, 4H), 2.28 (s, 3H)

ESI (+) MS m/z 466 (MH⁺)

ESI (+) HRMS calcd for C₂₈H₂₇N₅O₂+H⁺: 466.2237; found 466.2255

N-[6-(1-Benzyl-piperidin-4-yloxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 6)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.38 (s, 1H), 10.39 (s, 1H),7.99-7.94 (m, 2H), 7.59 (d, J=8.90 Hz, 1H), 7.38-7.24 (m, 5H), 7.04-6.99(m, 2H), 6.88 (d, J=2.07 Hz, 1H), 6.71 (dd, J=2.07, 8.90 Hz, 1H),4.52-4.44 (m, 1H), 3.53 (s, 2H), 3.34-3.32 (m, 4H), 2.78-2.65 (m, 2H),2.53-2.46 (m, 4H), 2.37-2.23 (m, 5H), 2.05-1.94 (m, 2H), 1.77-1.64 (m,2H)

ESI (+) MS m/z 525 (MH⁺)

ESI (+) HRMS calcd for C₃₁H₃₆N₆O₂+H⁺: 525.2972; found 525.2988

4-(4-Methyl-piperazin-1-yl)-N-[6-(2-phenoxy-ethoxy)-1H-indazol-3-yl]-benzamide(Cpd. 10)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.49 (s, 1H), 10.40 (s, 1H),7.99-7.95 (m, 2H), 7.62 (d, J=8.90 Hz, 1H), 7.37-7.29 (m, 2H), 7.05-7.00(m, 4H), 7.00-6.94 (m, 1H), 6.92 (d, J=2.07 Hz, 1H), 6.74 (dd, J=2.07,8.90 Hz, 1H), 4.41-4.36 (m, 4H), 3.35-3.30 (m, 4H), 2.52-2.46 (m, 4H),2.27 (s, 3H)

ESI (+) MS m/z 472 (MH⁺)

ESI (+) HRMS calcd for C₂₇N₅O₃H₂₉+H⁺: 472.2343; found 472.2357

N-[6-(1-Benzyl-piperidin-3-yloxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 12)

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.37 (s, 1H), 10.38 (s, 1H),7.99-7.93 (m, 2H), 7.58 (d, J=8.90 Hz, 1H), 7.36-7.22 (m, 5H), 7.05-6.98(m, 2H), 6.86 (d, J=1.83 Hz, 1H), 6.68 (dd, J=2.20, 8.90 Hz, 1H),4.51-4.42 (m, 1H), 3.55 (s, 2H), 3.35-3.30 (m, 4H), 3.02-2.95 (m, 1H),2.70-2.62 (m, 1H), 2.49-2.43 (m, 4H), 2.27 (s, 3H), 2.20-2.02 (m, 3H),1.81-1.71 (m, 1H), 1.65-1.53 (m, 1H), 1.48-1.36 (m, 1H)

ESI (+) MS m/z 525 (MH⁺)

ESI (+) HRMS calcd for C31N6O2H36+H⁺: 525.2972; found 525.2975

N-[6-(1-Benzyl-pyrrolidin-2-ylmethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 13)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.43 (s, 1H), 10.39 (s, 1H),7.99-7.93 (m, 2H), 7.59 (d, J=8.90 Hz, 1H), 7.38-7.21 (m, 5H), 7.04-6.99(m, 2H), 6.83 (d, J=1.95 Hz, 1H), 6.69 (dd, J=2.07, 8.90 Hz, 1H), 4.17(d, J=13.17 Hz, 1H), 4.04 (dd, J=5.49, 9.63 Hz, 1H), 3.90 (dd, J=6.58,9.63 Hz, 1H), 3.49 (d, J=13.17 Hz, 1H), 3.35-3.26 (m, 5H), 3.06-2.98 (m,1H), 2.88-2.83 (m, 1H), 2.49-2.44 (m, 4H), 2.32-2.24 (m, 1H), 2.24 (s,3H), 2.07-1.96 (m, 1H), 1.76-1.66 (m, 2H)

ESI (+) MS m/z 525 (MH⁺)

ESI (+) HRMS calcd for C₃₁N₆O₂H₃₆+H⁺: 525.2972; found 525.2969

4-(4-Methyl-piperazin-1-yl)-N-(6-phenoxy-1H-indazol-3-yl)-benzamide(Cpd. 2)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.57 (s, 1H), 10.54 (s, 1H),8.06-7.99 (m, 2H), 7.74 (d, J=8.78 Hz, 1H), 7.48-7.40 (m, 2H), 7.23-7.17(m, 1H), 7.13-7.06 (m, 4H), 6.90 (d, J=2.07 Hz, 1H), 6.84 (dd, J=2.07,8.90 Hz, 1H), 3.35-3.00 (m, 8H), 2.74 (s, 3H)

ESI (+) MS m/z 428 (MH⁺)

ESI (+) HRMS calcd for C₂₅N₅O₂H₂₅+H⁺: 428.2081; found 428.2092

N-[6-(3-Fluoro-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 3)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.64 (s, 1H), 10.53 (s, 1H),8.03-7.98 (m, 2H), 7.77 (d, J=8.78 Hz, 1H), 7.49-7.41 (m, 1H), 7.10-6.88(m, 6H), 6.86 (dd, J=2.07, 8.78 Hz, 1H), 3.35-3.24 (m, 4H), 2.90-2.65(m, 4H), 2.47 (bs, 3H)

ESI (+) MS m/z 446 (MH⁺)

ESI (+) HRMS calcd for C₂₅N₅O₂FH₂₄+H⁺: 446.1987; found 446.1981

N-[6-(4-Benzyloxy-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 4)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.46 (s, 1H), 10.47 (s, 1H),8.01-7.96 (m, 2H), 7.70 (d, J=8.90 Hz, 1H), 7.52-7.32 (m, 5H), 7.15-7.00(m, 6H), 6.81 (dd, J=2.19, 8.90 Hz, 1H), 6.74 (d, J=2.19 Hz, 1H), 5.13(s, 2H), 3.35-3.30 (m, 4H), 2.70-2.55 (m, 4H), 2.38 (bs, 3H)

ESI (+) MS m/z 534 (MH⁺)

ESI (+) HRMS calcd for C₃₂N₅O₃H₃₁+H⁺: 534.2500; found 534.2498

4-(4-Methyl-piperazin-1-yl)-N-[6-(4-phenoxy-phenoxy)-1H-indazol-3-yl]-benzamide(Cpd. 8)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53 (s, 1H), 10.48 (s, 1H),8.01-7.96 (m, 2H), 7.74 (d, J=8.78 Hz, 1H), 7.45-7.39 (m, 2H), 7.19-6.99(m, 9H), 6.89 (d, J=2.07 Hz, 1H), 6.85 (dd, J=2.07, 8.78 Hz, 1H),3.35-3.30 (m, 4H), 2.52-2.47 (m, 4H), 2.28 (bs, 3H)

ESI (+) MS m/z 520 (MH⁺)

ESI (+) HRMS calcd for C₃₁N₅O₃H₂₉+H⁺: 520.2343; found 520.2346

N-[6-(3-Benzyloxy-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 9)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.58 (s, 1H), 10.54 (s, 1H),8.05-7.99 (m, 2H), 7.74 (d, J=8.90 Hz, 1H), 7.47-7.29 (m, 6H), 7.12-7.06(m, 2H), 6.93 (d, J=1.95 Hz, 1H), 6.87-6.81 (m, 2H), 6.76-6.73 (m, 1H),6.65 (dd, J=2.19, 8.17 Hz, 1H), 5.11 (s, 2H), 3.35-2.80 (m, 8H), 2.65(bs, 3H)

ESI (+) MS m/z 534 (MH⁺)

ESI (+) HRMS calcd for C₃₂N₅O₃H₃₁+H⁺: 534.2500; found 534.2501

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 11)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (s, 1H) 10.38 (s, 1H) 7.95 (d,J=9.03 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.32-7.42 (m, 4H) 7.23-7.32 (m,1H) 7.00 (d, J=9.03 Hz, 2H) 6.85 (d, J=1.95 Hz, 1H) 6.71 (dd, J=8.91,2.07 Hz, 1H) 4.58 (s, 2H) 4.08-4.31 (m, 2H) 3.72-3.92 (m, 2H) 3.20-3.30(m, 4H) 2.40-2.48 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 486 (MH⁺)

ESI (+) HRMS calcd for C₂₈N₅O₃H₃₁+H⁺: 486.2500; found 486.2502

Preparation 10 4-(2-Benzyloxy-ethoxy)-2-fluoro-benzonitrile

Scheme 2, Step Jc)

A mixture of 2-fluoro-4-hydroxy-benzonitrile (4.57 g, 33.3 mmol), K₂CO₃(13.8 g, 99.9 mmol) and benzyl 2-bromoethyl ether (5.79 ml, 36.6 mmol)in dry DMF (15 ml) was stirred at 70° C. for 6 h. The reaction mixturewas cooled to r.t., poured into 300 ml of water and extracted with EtOAc(2×100 ml). The organic layers were combined, dried over sodium sulfateand evaporated to dryness. The crude residue was purified bychromatography (Biotage SP1 Flash Purification system) on a silica gelcartridge (Biotage SNAP 100 g) eluting with a gradient from hexane/EtOAc100:0 to 60:40 over 20 CV, affording 8.79 g (yield: 97%) of the titlecompound as a colourless oil.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.75-7.90 (m, 1H) 7.26-7.38 (m, 5H)7.19 (dd, J=11.96, 2.44 Hz, 1H) 6.99 (dd, J=8.79, 2.32 Hz, 1H) 4.55 (s,2H) 4.22-4.34 (m, 2H) 3.65-3.87 (m, 2H)

ESI (+) MS m/z 272 (MH⁺)

Operating in an analogous way, the following compounds were obtained:

2-Fluoro-4-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-benzonitrile

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.82 (t, J=8.33 Hz, 1H) 7.71 (d,J=8.06 Hz, 2H) 7.55 (d, J=7.88 Hz, 2H) 7.19 (dd, J=12.00, 2.29 Hz, 1H)7.00 (dd, J=8.70, 2.29 Hz, 1H) 4.66 (s, 2H) 4.28-4.31 (m, 2H) 3.79-3.84(m, 2H)

ESI (+) MS m/z 340 (MH⁺)

ESI (+) HRMS calcd for C₁₇H₁₃F₄NO₂+Na⁺: 362.0774; found 362.0771

2-Fluoro-4-[2-(4-fluoro-benzyloxy)-ethoxy]-benzonitrile

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.82 (t, J=8.43 Hz, 1H) 7.31-7.40(m, 2H) 7.13-7.23 (m, 3H) 6.99 (dd, J=8.79, 2.20 Hz, 1H) 4.53 (s, 2H)4.25-4.29 (m, 2H) 3.75-3.79 (m, 2H)

ESI (+) MS m/z 290 (MH⁺)

ESI (+) HRMS calcd for C₁₆H₁₃F₂NO₂+Na⁺: 312.0806; found 312.0812

2-Fluoro-4-[2-(3-trifluoromethyl-benzyloxy)-ethoxy]-benzonitrile

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.79-7.85 (m, 1H) 7.55-7.67 (m, 4H)7.18 (dd, J=11.96, 2.32 Hz, 1H) 6.99 (dd, J=8.79, 2.44 Hz, 1H) 4.65 (s,2H) 4.29-4.34 (m, 2H) 3.80-3.85 (m, 2H)

ESI (+) MS m/z 340 (MH⁺)

ESI (+) HRMS calcd for C₁₇H₁₃F₄NO₂+H⁺: 340.0955; found 340.0948

2-Fluoro-4-[2-(2-fluoro-benzyloxy)-ethoxy]-benzonitrile

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.82 (t, J=8.33 Hz, 1H) 7.44 (td,J=7.65, 1.74 Hz, 1H) 7.33-7.39 (m, 1H) 7.15-7.23 (m, 3H) 6.98 (dd,J=8.79, 2.20 Hz, 1H) 4.60 (s, 2H) 4.26-4.30 (m, 2H) 3.79-3.83 (m, 2H)

ESI (+) MS m/z 290 (MH⁺)

ESI (+) HRMS calcd for C₁₆H₁₃F₂NO₂+H⁺: 290.0987; found 290.0995

2-Fluoro-4-[2-(4-methoxy-benzyloxy)-ethoxy]-benzonitrile

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.81 (dd, J=8.61, 8.06 Hz, 1H)7.21-7.31 (m, 2H) 7.18 (dd, J=11.90, 2.38 Hz, 1H) 6.98 (dd, J=8.79, 2.38Hz, 1H) 6.85-6.91 (m, 2H) 4.46 (s, 2H) 4.21-4.31 (m, 2H) 3.63-3.81 (m,5H)

ESI (+) MS m/z 302 (MH⁺)

ESI (+) HRMS calcd for C₁₇H₁₆FNO₃+Na⁺: 324.1006; found 324.1008

2-Fluoro-4-[2-(pyridin-4-ylmethoxy)-ethoxy]-benzonitrile

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 8.50-8.54 (m, 2H) 7.83 (t, J=8.33Hz, 1H) 7.32 (d, J=5.49 Hz, 2H) 7.20 (dd, J=11.91, 2.20 Hz, 1H) 7.01(dd, J=8.79, 2.38 Hz, 1H) 4.61 (s, 2H) 4.30-4.33 (m, 2H) 3.81-3.84 (m,2H)

ESI (+) MS m/z 273 (MH⁺)

ESI (+) HRMS calcd for C₁₅H₁₃FN₂O₂+H⁺: 273.1034; found 273.1031

2-Fluoro-4-((E)-3-phenyl-allyloxy)-benzonitrile

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.84 (t, J=8.33 Hz, 1H) 7.44-7.53(m, 2H) 7.36 (t, J=7.60 Hz, 2H) 7.26-7.31 (m, 1H) 7.23 (dd, J=11.90,2.38 Hz, 1H) 7.04 (dd, J=8.79, 2.38 Hz, 1H) 6.80 (d, J=15.93 Hz, 1H)6.50 (dt, J=15.93, 6.04 Hz, 1H) 4.86 (dd, J=6.04, 1.10 Hz, 2H)

ESI (+) MS m/z 254 (MH⁺)

ESI (+) HRMS calcd for C₁₆H₁₂FNO+Na⁺: 276.0795; found 276.0795

Preparation 11 6-(2-Benzyloxy-ethoxy)-1H-indazol-3-ylamine

Scheme 2, Step K)

A mixture of 4-(2-benzyloxy-ethoxy)-2-fluoro-benzonitrile (8.79 g, 32.4mmol) and hydrazine monohydrate (4.72 ml, 97.2 mmol) in n-butanol (15ml) was stirred at 120° C. for 8 h. The reaction mixture was cooled tor.t., treated with 250 ml of water and stirred for 30 min. Theprecipitated solid was filtered, washed with water and dried in oven at50° C. under high vacuum, affording 9.0 g of the title compound as whitecrystals (yield: 98%).

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.13 (s, 1H) 7.52 (d, J=8.67 Hz,1H) 7.33-7.38 (m, 4H) 7.25-7.32 (m, 1H) 6.64 (d, J=1.83 Hz, 1H) 6.54(dd, J=8.67, 2.07 Hz, 1H) 5.26 (bs, 2H) 4.57 (s, 2H) 4.12-4.16 (m, 2H)3.77-3.80 (m, 2H)

ESI (+) MS m/z 284 (MH⁺)

Operating in an analogous way, the following compounds were obtained:

6-[2-(4-Trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-ylamine

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.12 (s, 1H) 7.72 (d, J=8.06 Hz,2H) 7.58 (d, J=8.06 Hz, 2H) 7.52 (d, J=8.79 Hz, 1H) 6.65 (d, J=1.83 Hz,1H) 6.55 (dd, J=8.70, 2.11 Hz, 1H) 5.19 (s, 2H) 4.68 (s, 2H) 4.14-4.19(m, 2H) 3.81-3.85 (m, 2H)

ESI (+) MS m/z 352 (MH⁺)

ESI (+) HRMS calcd for C₁₇H₁₆F₃N₃O₂+H⁺: 352.1268; found 352.1278

6-[2-(4-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-ylamine

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.12 (s, 1H) 7.52 (d, J=8.79 Hz,1H) 7.39 (dd, J=8.52, 5.77 Hz, 2H) 7.14-7.20 (m, 2H) 6.64 (d, J=2.01 Hz,1H) 6.53 (dd, J=8.70, 2.11 Hz, 1H) 5.19 (s, 2H) 4.55 (s, 2H) 4.10-4.15(m, 2H) 3.76-3.80 (m, 2H)

ESI (+) MS m/z 302 (MH⁺)

ESI (+) HRMS calcd for C₁₆H₁₆FN₃O₂+H⁺: 302.1300; found 302.1306

6-[2-(3-Trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-ylamine

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.13 (s, 1H) 7.71 (s, 1H) 7.57-7.69(m, 3H) 7.48-7.54 (m, 1H) 6.65 (d, J=1.95 Hz, 1H) 6.54 (dd, J=8.79, 2.07Hz, 1H) 5.21 (br. s., 2H) 4.68 (s, 2H) 4.13-4.19 (m, 2H) 3.80-3.87 (m,2H)

ESI (+) MS m/z 352 (MH⁺)

ESI (+) HRMS calcd for C₁₇H₁₆F₃N₃O₂+H⁺: 352.1268; found 352.1274

6-[2-(2-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-ylamine

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.12 (s, 1H) 7.52 (d, J=8.79 Hz,1H) 7.45-7.50 (m, 1H) 7.33-7.40 (m, 1H) 7.16-7.24 (m, 2H) 6.64 (d,J=1.83 Hz, 1H) 6.53 (dd, J=8.70, 2.11 Hz, 1H) 5.19 (s, 2H) 4.63 (s, 2H)4.13 (dd, J=5.40, 3.75 Hz, 2H) 3.82 (dd, J=5.31, 3.85 Hz, 2H)

ESI (+) MS m/z 302 (MH⁺)

ESI (+) HRMS calcd for C₁₆H₁₆FN₃O₂+H⁺: 302.1300; found 302.1302

6-[2-(4-Methoxy-benzyloxy)-ethoxy]-1H-indazol-3-ylamine

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.11 (s, 1H) 7.51 (d, J=8.79 Hz,1H) 7.27 (d, J=8.61 Hz, 2H) 6.91 (d, J=8.61 Hz, 2H) 6.63 (d, J=1.65 Hz,1H) 6.53 (dd, J=8.79, 1.83 Hz, 1H) 5.19 (s, 2H) 4.48 (s, 2H) 4.09-4.13(m, 2H) 3.68-3.78 (m, 5H)

ESI (+) MS m/z 314 (MH⁺)

ESI (+) HRMS calcd for C₁₇H₁₉N₃O₃+H⁺: 314.1499; found 314.1502

6-[2-(Pyridin-4-ylmethoxy)-ethoxy]-1H-indazol-3-ylamine

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.13 (s, 1H) 8.51-8.55 (m, 2H) 7.52(d, J=8.79 Hz, 1H) 7.35 (d, J=5.86 Hz, 2H) 6.65 (d, J=1.83 Hz, 1H) 6.55(dd, J=8.61, 2.01 Hz, 1H) 5.20 (s, 2H) 4.63 (s, 2H) 4.15-4.19 (m, 2H)3.81-3.88 (m, 2H)

ESI (+) MS m/z 285 (MH⁺)

ESI (+) HRMS calcd for C₁₅H₁₆N₄O₂+H⁺: 285.1346; found 285.1339

6-((E)-3-Phenyl-allyloxy)-1H-indazol-3-ylamine

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.13 (s, 1H) 7.54 (d, J=8.61 Hz,1H) 7.49 (d, J=7.14 Hz, 2H) 7.35 (t, J=7.51 Hz, 2H) 7.24-7.30 (m, 1H)6.77 (d, J=15.93 Hz, 1H) 6.70 (s, 1H) 6.57-6.60 (m, 1H) 6.53 (dt,J=15.93, 5.68 Hz, 1H) 5.20 (s, 2H) 4.73 (d, J=5.31 Hz, 2H)

ESI (+) MS m/z 266 (MH⁺)

ESI (+) HRMS calcd for C₁₆H₁₅N₃O+H⁺: 266.1288; found 266.1286

EXAMPLE 2N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 11)

Scheme 2, Step L)

A stirred suspension of 4-(4-methyl-piperazin-1-yl)-benzoyl chloridehydrochloride, prepared from 4.55 g (20.7 mmol) of4-(4-methyl-piperazin-1-yl)-benzoic acid as described above inpreparation 3, in dry pyridine (50 ml) was treated dropwise, at 0° C.,under argon atmosphere, with a solution of6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylamine (5.31 g, 18.8 mmol) in 80 mlof dry pyridine. The reaction mixture was allowed to warm to r.t. understirring overnight, then concentrated to 30 ml by rotary evaporation,poured into 500 ml of saturated solution of NaHCO₃ and extracted with300+100 ml of DCM. The organic layers were combined, dried over sodiumsulfate and evaporated to dryness. The crude residue was treated with200 ml of EtOAc and stirred at reflux for 2 h. After cooling to r.t. thesolid was filtered, washed with EtOAc and dried in oven at 50° C. underhigh vacuum to afford 5.23 g (yield: 57%) of the title compound as awhite solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (s, 1H) 10.38 (s, 1H) 7.95 (d,J=9.03 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.41 (m, 4H) 7.25-7.32 (m,1H) 7.00 (d, J=9.15 Hz, 2H) 6.85 (d, J=2.08 Hz, 1H) 6.71 (dd, J=8.91,2.20 Hz, 1H) 4.58 (s, 2H) 4.15-4.25 (m, 2H) 3.70-3.88 (m, 2H) 3.25-3.35(m, 4H) 2.42-2.48 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 486 (MH⁺)

ESI (+) HRMS calcd for C₂₈N₅O₃H₃₁+H⁺: 486.2500; found 486.2501

Operating in an analogous way, the following compounds were obtained:

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-dimethylaminomethyl-benzamide(Cpd. 21)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51 (s, 1H) 10.65 (s, 1H) 8.02 (d,J=8.30 Hz, 2H) 7.61 (d, J=8.91 Hz, 1H) 7.43 (d, J=8.42 Hz, 2H) 7.33-7.38(m, 4H) 7.26-7.32 (m, 1H) 6.87 (d, J=1.95 Hz, 1H) 6.73 (dd, J=8.91, 2.08Hz, 1H) 4.59 (s, 2H) 4.19-4.23 (m, 2H) 3.79-3.84 (m, 2H) 3.47 (s, 2H)2.17 (s, 6H)

ESI (+) MS m/z 445 (MH⁺)

ESI (+) HRMS calcd for C₂₆N₄O₃H₂₈+H⁺: 445.2234; found 445.2224

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-benzamide(Cpd. 22)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.48 (s, 1H) 10.52 (s, 1H)7.99-8.04 (m, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.40 (m, 4H) 7.26-7.31(m, 1H) 7.04-7.09 (m, 2H) 6.86 (d, J=1.95 Hz, 1H) 6.72 (dd, J=8.91, 2.20Hz, 1H) 4.58 (s, 2H) 4.44-4.54 (m, 1H) 4.17-4.23 (m, 2H) 3.79-3.86 (m,2H) 2.57-2.67 (m, 2H) 2.14-2.25 (m, 5H) 1.91-2.02 (m, 2H) 1.59-1.75 (m,2H)

ESI (+) MS m/z 501 (MH⁺)

ESI (+) HRMS calcd for C₂₉N₄O₄H₃₂+H⁺: 501.2497; found 501.2482

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-3-(4-methyl-piperazin-1-yl)-benzamidehydrochloride (Cpd. 29)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56 (br. s., 1H) 10.69 (s, 1H)10.17 (br. s., 1H) 7.66 (br. s, 1H) 7.61 (d, J=8.79 Hz, 1H) 7.55 (d,J=7.69 Hz, 1H) 7.41 (dd, J=8.43, 7.69 Hz, 1H) 7.32-7.39 (m, 4H)7.27-7.31 (m, 1H) 7.24 (dd, J=8.43, 1.83 Hz, 1H) 6.88 (d, J=1.83 Hz, 1H)6.73 (dd, J=8.79 Hz, 2.01 Hz, 1H) 4.8 (s, 2H) 4.16-4.24 (m, 2H)3.91-4.02 (m, 2H) 3.78-3.84 (m, 2H) 3.50-3.56 (m, 2H) 3.01-3.23 (m, 4H)2.85 (d, J=4.21 Hz, 3H)

ESI (+) MS m/z 486 (MH⁺)

ESI (+) HRMS calcd for C₂₈H₃₁N₅O₃+H⁺: 486.2500; found 486.2514

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-2-fluoro-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 38)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.45 (s, 1H) 10.06 (d, J=3.66 Hz,1H) 7.61-7.69 (m, 2H) 7.34-7.39 (m, 4H) 7.27-7.31 (m, 1H) 6.78-6.86 (m,3H) 6.72 (dd, J=8.88, 2.11 Hz, 1H) 4.58 (s, 2H) 4.18-4.21 (m, 2H)3.79-3.84 (m, 2H) 3.29-3.33 (m, 4H) 2.40-2.45 (m, 4H) 2.22 (s, 3H)

ESI (+) MS m/z 504 (MH⁺)

ESI (+) HRMS calcd for C₂₈H₃₀FN₅O₃+H⁺: 504.2406; found 504.2383

4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide(Cpd. 33)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.45 (s, 1H) 10.38 (s, 1H) 7.95 (d,J=8.97 Hz, 2H) 7.72 (d, J=8.06 Hz, 2H) 7.57-7.61 (m, 3H) 7.00 (d, J=8.97Hz, 2H) 6.86 (d, J=1.83 Hz, 1H) 6.72 (dd, J=8.88, 2.11 Hz, 1H) 4.70 (s,2H) 4.20-4.25 (m, 2H) 3.82-3.89 (m, 2H) 3.27-3.35 (m, 4H) 2.40-2.47 (m,4H) 2.23 (s, 3H)

ESI (+) MS m/z 554 (MH⁺)

ESI (+) HRMS calcd for C₂₉H₃₀F₃N₅O₃+H⁺: 554.2374; found 554.2389

N-{6-[2-(4-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 32)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (s, 1H) 10.38 (s, 1H) 7.95 (d,J=8.97 Hz, 2H) 7.59 (d, J=8.79 Hz, 1H) 7.37-7.44 (m, 2H) 7.15-7.21 (m,2H) 7.00 (d, J=8.97 Hz, 2H) 6.85 (d, J=2.01 Hz, 1H) 6.71 (dd, J=8.88,2.11 Hz, 1H) 4.56 (s, 2H) 4.18-4.22 (m, 2H) 3.79-3.82 (m, 2H) 3.27-3.37(m, 4H) 2.43-2.47 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 504 (MH⁺)

ESI (+) HRMS calcd for C₂₈H₃₀FN₅O₃+H⁺: 504.2406; found 504.2414

4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(3-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide(Cpd. 34)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.45 (s, 1H) 10.38 (s, 1H) 7.95 (d,J=9.03 Hz, 2H) 7.72 (s, 1H) 7.63-7.70 (m, 2H) 7.56-7.63 (m, 2H) 7.00 (d,J=9.15 Hz, 2H) 6.86 (d, J=2.08 Hz, 1H) 6.71 (dd, J=8.91, 2.07 Hz, 1H)4.70 (s, 2H) 4.20-4.24 (m, 2H) 3.83-3.89 (m, 2H) 3.24-3.40 (m, 4H)2.42-2.48 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 554 (MH⁺)

ESI (+) HRMS calcd for C₂₉H₃₀F₃N₅O₃+H⁺: 554.2374; found 554.2371

N-{6-[2-(2-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 30)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (s, 1H) 10.38 (s, 1H) 7.95 (d,J=8.97 Hz, 2H) 7.58 (d, J=8.79 Hz, 1H) 7.46-7.51 (m, 1H) 7.35-7.40 (m,1H) 7.16-7.25 (m, 2H) 7.00 (d, J=9.16 Hz, 2H) 6.85 (d, J=1.83 Hz, 1H)6.70 (dd, J=8.88, 2.11 Hz, 1H) 4.64 (s, 2H) 4.18-4.21 (m, 2H) 3.82-3.87(m, 2H) 3.22-3.31 (m, 4H) 2.40-2.48 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 504 (MH⁺)

ESI (+) HRMS calcd for C₂₈H₃₀FN₅O₃+H⁺: 504.2406; found 504.2409

N-{6-[2-(4-Methoxy-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 40)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (s, 1H) 10.38 (s, 1H) 7.95 (d,J=8.97 Hz, 2H) 7.59 (d, J=8.97 Hz, 1H) 7.28 (d, J=8.61 Hz, 2H) 7.00 (d,J=8.97 Hz, 2H) 6.85-6.93 (m, 2H) 6.84 (d, J=2.01 Hz, 1H) 6.70 (dd,J=8.88, 2.11 Hz, 1H) 4.50 (s, 2H) 4.12-4.24 (m, 2H) 3.76-3.80 (m, 2H)3.74 (s, 3H) 3.27-3.34 (m, 4H) 2.42-2.47 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 516 (MH⁺)

ESI (+) HRMS calcd for C₂₉H₃₃N₅O₄+H⁺: 516.2606; found 516.2617

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-2,4-bis-(4-methyl-piperazin-1-yl)-benzamide(Cpd. 43)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.65 (s, 1H) 12.41 (s, 1H)8.01-8.05 (m, 1H) 7.96-8.00 (m, 1H) 7.34-7.39 (m, 4H) 7.26-7.32 (m, 1H)6.84-6.89 (m, 2H) 6.81-6.83 (m, 1H) 6.68-6.73 (m, 1H) 4.58 (s, 2H)4.17-4.21 (m, 2H) 3.79-3.83 (m, 2H) 3.27-3.32 (m, 4H) 3.01-3.06 (m, 4H)2.56-2.71 (m, 4H) 2.41-2.48 (m, 4H) 2.25 (s, 3H) 2.23 (s, 3H)

ESI (+) MS m/z 584 (MH⁺)

ESI (+) HRMS calcd for C₃₃H₄₁N₇O₃+H⁺: 584.3344; found 584.3340

4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(pyridin-4-ylmethoxy)-ethoxy]-1H-indazol-3-yl}-benzamide(Cpd. 35)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.45 (s, 1H) 10.38 (s, 1H) 8.53 (d,J=4.58 Hz, 2H) 7.95 (d, J=8.06 Hz, 2H) 7.60 (d, J=8.97 Hz, 1H) 7.35 (d,J=4.58 Hz, 2H) 7.00 (d, J=8.24 Hz, 2H) 6.87 (s, 1H) 6.72 (d, J=8.97 Hz,1H) 4.65 (s, 2H) 4.21-4.25 (m, 2H) 3.85-3.88 (m, 2H) 3.27-3.37 (m, 4H)2.43-2.48 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 487 (MH⁺)

ESI (+) HRMS calcd for C₂₇H₃₀N₆O₃+H⁺: 487.2452; found 487.2450

4-(4-Methyl-piperazin-1-yl)-N-[6-((E)-3-phenyl-allyloxy)-1H-indazol-3-yl]-benzamide(Cpd. 39)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.45 (s, 1H) 10.39 (s, 1H) 7.95 (d,J=8.97 Hz, 2H) 7.61 (d, J=8.97 Hz, 1H) 7.48-7.52 (m, 2H) 7.36 (t, J=7.69Hz, 2H) 7.26-7.31 (m, 1H) 7.00 (d, J=8.97 Hz, 2H) 6.91 (d, J=1.83 Hz,1H) 6.81 (d, J=16.12 Hz, 1H) 6.75 (dd, J=8.97, 2.20 Hz, 1H) 6.56 (dt,J=15.98, 5.75 Hz, 1H) 4.80 (d, J=5.13 Hz, 2H) 3.28-3.32 (m, 4H)2.43-2.47 (m, 4H) 2.23 (s, 3H)

ESI (+) MS m/z 468 (MH⁺)

ESI (+) HRMS calcd for C₂₈H₂₉N₅O₂+H⁺: 468.2394; found 468.2394

Preparation 12N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-bromo-benzamide

Scheme 2, Step M)

To a stirred solution of 6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylamine(3.0 g, 10.6 mmol) in 30 ml of dry pyridine, at 0° C., under argonatmosphere, was added portionwise 4-bromo-benzoyl chloride (2.32 g, 10.6mmol). The reaction mixture was allowed to warm to r.t. under stirringovernight then evaporated to dryness. The residue was treated with 50 mlof MeOH and 25 ml of 2N NaOH and stirred at r.t. for 1 h. The mixturewas concentrated to ca. 10 ml by rotary evaporation, diluted with 200 mlof water, stirred for 15 min at r.t. and the suspended solid filteredand washed with water. After drying under vacuum, the crude solid waspurified by chromatography (Biotage SP1 Flash Purification system) on asilica gel cartridge (Biotage SNAP 100 g) using DCM as eluant A andDCM/MeOH 9:1 as eluant B. Elution with a gradient from A/B 100:0 to70:30 over 25 CV gave a pink solid that was triturated with EtOAc (50ml), filtered, washed with EtOAc and dried affording 3.01 g (yield: 61%)of the title compound as a whitish solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54 (s, 1H) 10.81 (s, 1H) 7.99 (d,J=8.54 Hz, 2H) 7.75 (d, J=8.67 Hz, 2H) 7.62 (d, J=8.91 Hz, 1H) 7.21-7.42(m, 5H) 6.87 (d, J=1.95 Hz, 1H) 6.73 (dd, J=8.97, 2.14 Hz, 1H) 4.58 (s,2H) 4.11-4.29 (m, 2H) 3.71-3.98 (m, 2H)

ESI (+) MS m/z 467 (MH⁺)

Preparation 13 2-(4-trifluoromethyl-benzyloxy)-ethanol

Under argon atmosphere, at r.t., sodium hydride (60% dispersion inmineral oil, 1.92 g, 48 mmol) was stirred with n-hexane (ca. 10 ml). Thehexane/mineral oil solution was drawn off and discarded and the leftsodium hydride was treated with 20 ml of dry THF. Ethylene glycol (17.8ml, 320 mmol) was then slowly dropped at r.t. (caution: hydrogenevolution) and the mixture stirred at r.t. for 1.5 hours. After heatingup to reflux (80° C. oil bath) a solution of1-bromomethyl-4-trifluoromethyl-benzene (7.6 g, 32 mmol) in 20 ml of dryTHF was added and the reaction mixture stirred at reflux for 2.5 hours.After cooling to r.t., 100 ml of ammonium chloride saturated solutionwas added. The organic layer was separated, washed with 50 ml of water,dried over sodium sulfate and evaporated to dryness. The crude residuewas purified by flash chromatography (Biotage SP1 Flash Purificationsystem) on a silica gel cartridge (Varian SF40-120 g) using n-hexane aseluant A and EtOAc as eluant B. Elution with a gradient from A/B 75:25to 70:30 over 2 CV then from 70:30 to 0:100 over 2 CV then 100% of Bafforded 5.9 g (yield: 84%) of the title compound as a yellow oil(yield: 93%).

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.71 (d, J=8.06 Hz, 2H) 7.56 (d,J=7.88 Hz, 2H) 4.66 (t, J=5.49 Hz, 1H) 4.60 (s, 2H) 3.56 (q, J=5.31 Hz,2H) 3.48-3.51 (m, 2H)

ESI (+) MS m/z 221 (MH⁺)

ESI (+) HRMS calcd for C₁₀H₁₁F₃O₂+Na⁺: 243.0603; found 243.0594

Operating in an analogous way, the following compounds were obtained:

2-(4-Fluoro-benzyloxy)-ethanol

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.37 (dd, J=8.43, 5.86 Hz, 2H) 7.16(t, J=8.88 Hz, 2H) 4.62 (t, J=5.49 Hz, 1H) 4.46 (s, 2H) 3.53 (q, J=5.19Hz, 2H) 3.41-3.47 (m, 2H)

ESI (+) MS m/z 171 (MH⁺)

ESI (+) HRMS calcd for C₉H₁₁FO₂+Na⁺: 193.0635; found 193.0635

2-(3-Trifluoromethyl-benzyloxy)-ethanol

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.55-7.72 (m, 4H) 4.66 (t, J=5.49Hz, 1H) 4.59 (s, 2H) 3.53-3.59 (m, 2H) 3.47-3.52 (m, 2H)

ESI (+) MS m/z 221 (MH⁺)

2-(2-Fluoro-benzyloxy)-ethanol

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.47 (td, J=7.51, 1.65 Hz, 1H) 7.36(tdd, J=7.76, 7.76, 5.63, 1.74 Hz, 1H) 7.14-7.21 (m, 2H) 4.63 (t, J=5.49Hz, 1H) 4.54 (s, 2H) 3.51-3.55 (m, 2H) 3.46-3.50 (m, 2H)

ESI (+) MS m/z 171 (MH⁺)

ESI (+) HRMS calcd for C₉H₁₁FO₂+Na⁺: 193.0635; found 193.0635

2-(4-Methoxy-benzyloxy)-ethanol

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.25 (d, J=8.79 Hz, 2H) 6.90 (d,J=8.61 Hz, 2H) 4.58 (t, J=5.59 Hz, 1H) 4.40 (s, 2H) 3.74 (s, 3H) 3.51(q, J=5.31 Hz, 2H) 3.39-3.43 (m, 2H)

ESI (+) MS m/z 183 (MH⁺)

ESI (+) HRMS calcd for C₁₀H₁₄O₃+Na⁺: 205.0835; found 205.0835

2-(Pyridin-4-ylmethoxy)-ethanol

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 8.51-8.54 (m, 2H) 7.32-7.36 (m, 2H)4.68 (t, J=5.49 Hz, 1H) 4.55 (s, 2H) 3.57 (q, J=5.25 Hz, 2H) 3.46-3.52(m, 2H)

ESI (+) MS m/z 154 (MH⁺)

ESI (+) HRMS calcd for C₈H₁₁NO₂+H⁺: 154.0863; found 154.0857

Preparation 14 Methanesulfonic acid2-(4-trifluoromethyl-benzyloxy)-ethyl ester

To a solution of 2-(4-trifluoromethyl-benzyloxy)-ethanol (1.0 g, 4.5mmol) in dry DCM (20 ml) and DIPEA (2.36 ml, 13.5 mmol), at 0° C., underargon atmosphere, was added methanesulfonyl chloride (421 μl, 5.4 mmol).The reaction mixture was stirred at 0° C. for 10 minutes, then theice-bath removed and the stirring continued for 2 hours at r.t. Themixture was then diluted with 70 ml of DCM and washed with 50 ml ofNaHCO₃ saturated solution, 100 ml of water, 100 ml of 2N HCl and 100 mlof water, dried over sodium sulfate and evaporated to dryness affording1.35 g (yield: quantitative) of methanesulfonic acid2-(4-trifluoromethyl-benzyloxy)-ethyl ester as a brown oil that was usedas such for the next step without further purification.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.73 (d, J=8.06 Hz, 2H) 7.57 (d,J=7.88 Hz, 2H) 4.64 (s, 2H) 4.35-4.42 (m, 2H) 3.71-3.78 (m, 2H) 3.18 (s,3H)

ESI (+) MS m/z 299 (MH⁺)

ESI (+) HRMS calcd for C₁₁H₁₃F₃O₄S+Na⁺: 321.0379; found 321.0380

Operating in an analogous way, the following compounds were obtained:

Methanesulfonic acid 2-(4-fluoro-benzyloxy)-ethyl ester

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.30-7.44 (m, 2H) 7.12-7.23 (m, 2H)4.51 (s, 2H) 4.29-4.38 (m, 2H) 3.63-3.75 (m, 2H) 3.17 (s, 3H)

ESI (+) MS m/z 249 (MH⁺)

ESI (+) HRMS calcd for C₁₁H₁₃F₃O₄S+Na⁺: 271.0411; found 271.0412

Methanesulfonic acid 2-(3-trifluoromethyl-benzyloxy)-ethyl ester

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.55-7.72 (m, 4H) 4.64 (s, 2H)4.34-4.42 (m, 2H) 3.71-3.78 (m, 2H) 3.18 (s, 3H)

ESI (+) MS m/z 299 (MH⁺)

Methanesulfonic acid 2-(2-fluoro-benzyloxy)-ethyl ester

¹H-NMR (400 MHz), δ (ppm, DMSO-d₁₆): 7.44-7.48 (m, 1H) 7.34-7.41 (m, 1H)7.16-7.25 (m, 2H) 4.59 (s, 2H) 4.34-4.36 (m, 2H) 3.71-3.75 (m, 2H) 3.16(s, 3H)

ESI (+) MS m/z 249 (MH⁺)

ESI (+) HRMS calcd for C₁₁H₁₃F₃O₄S+Na⁺: 271.0411; found 271.0411

Methanesulfonic acid 2-(4-methoxy-benzyloxy)-ethyl ester

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.26 (d, J=8.79 Hz, 2H) 6.76-7.00(m, 2H) 4.45 (s, 2H) 4.28-4.35 (m, 2H) 3.74 (s, 3H) 3.60-3.68 (m, 2H)3.16 (s, 3H)

ESI (+) MS m/z 261 (MH⁺)

ESI (+) HRMS calcd for C₁₁H₁₆O₅S+Na⁺: 283.0610; found 283.0614

Methanesulfonic acid 2-(pyridin-4-ylmethoxy)-ethyl ester

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 8.51-8.57 (m, 2H) 7.34 (d, J=5.86Hz, 2H) 4.60 (s, 2H) 4.36-4.41 (m, 2H) 3.72-3.78 (m, 2H) 3.19 (s, 3H)

ESI (+) MS m/z 232 (MH⁺)

ESI (+) HRMS calcd for C₉H₁₃NO₄S+H⁺: 232.0638; found 232.0636

EXAMPLE 3N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-dimethylamino-piperidin-1-yl)-benzamide(Cpd. 15)

Scheme 2, Step N)

A solution ofN-[6-(2-benzyloxy-ethoxy)-1H-indazol-3-yl]-4-bromo-benzamide (1.3 g,2.79 mmol) and 4-dimethylamino-piperidine (1.18 ml, 8.37 mmol) in dryTHF (20 ml) was degassed by three vacuum-argon atmosphere cycles andtreated at r.t., under argon atmosphere, with Pd₂(dba)₃ (50 mg),2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (50 mg) and 1MLiHMDS in THF (22.3 ml, 22.3 mmol). The reaction mixture was heated toreflux and stirred for 15 min then cooled to r.t., poured into 200 ml ofwater and extracted with 200 ml of EtOAc. The organic layer wasseparated, dried over sodium sulfate and evaporated to dryness. Thecrude residue was purified by chromatography (Biotage SP1 FlashPurification system) on a silica gel cartridge (Varian SF40-120 g) usingDCM as eluant A and DCM/7N NH₃ in MeOH 10:1 as eluant B. Elution with agradient from A/B 100:0 to 0:100 over 10 CV, followed by an isocraticelution with eluant B (5 CV), gave a yellow solid that was trituratedwith EtOAc (15 ml), filtered, washed with EtOAc and dried affording 1.04g (yield: 73%) of the title compound as a white solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (s, 1H) 10.35 (s, 1H)7.85-8.01 (m, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.40 (m, 4H) 7.25-7.32(m, 1H) 6.93-7.06 (m, 2H) 6.85 (d, J=2.07 Hz, 1H) 6.71 (dd, J=8.91, 2.08Hz, 1H) 4.58 (s, 2H) 4.14-4.26 (m, 2H) 3.86-3.98 (m, 2H) 3.73-3.85 (m,2H) 2.74-2.90 (m, 2H) 2.23-2.35 (m, 1H) 2.19 (s, 6H) 1.77-1.87 (m, 2H)1.35-1.50 (m, 2H)

ESI (+) MS m/z 514 (MH⁺)

ESI (+) HRMS calcd for C₃₀N₅O₃H₃₅+H⁺: 514.2813; found 514.2817

Operating in an analogous way, the following compounds were obtained:

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-benzamide(Cpd. 16)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.41 (s, 1H) 10.27 (s, 1H)7.89-7.96 (m, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.38 (m, 4H) 7.25-7.32(m, 1H) 6.85 (d, J=2.07 Hz, 1H) 6.68-6.76 (m, 3H) 4.58 (s, 2H) 4.17-4.22(m, 2H) 3.78-3.85 (m, 2H) 3.50 (t, J=7.08 Hz, 2H) 2.99 (s, 3H) 2.40 (t,J=7.02 Hz, 2H) 2.19 (s, 6H)

ESI (+) MS m/z 488 (MH⁺)

ESI (+) HRMS calcd for C₂₈N₅O₃H₃₃+H⁺: 488.2656; found 488.2654

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide(Cpd. 17)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.41 (s, 1H) 10.26 (s, 1H)7.90-7.95 (m, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.34-7.40 (m, 4H) 7.27-7.32(m, 1H) 6.85 (d, J=2.07 Hz, 1H) 6.72-6.77 (m, 2H) 6.70 (dd, J=8.91, 2.20Hz, 1H) 4.58 (s, 2H) 4.17-4.23 (m, 2H) 3.79-3.83 (m, 2H) 3.43 (t, J=7.14Hz, 2H) 2.98 (s, 3H) 2.23 (t, J=6.84 Hz, 2H) 2.14 (s, 6H) 1.61-1.71 (m,2H)

ESI (+) MS m/z 502 (MH⁺)

ESI (+) HRMS calcd for C₂₉N₅O₃H₃₅+H⁺: 502.2813; found 502.2794

4-{4-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-ylcarbamoyl]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Cpd. 18)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.45 (s, 1H) 10.40 (s, 1H)7.95-7.99 (m, 2H) 7.59 (d, J=9.03 Hz, 1H) 7.34-7.38 (m, 4H) 7.26-7.33(m, 1H) 6.98-7.05 (d, J=9.15 Hz, 2H) 6.85 (d, J=2.20 Hz, 1H) 6.71 (dd,J=8.91, 2.07 Hz, 1H) 4.58 (s, 2H) 4.16-4.23 (m, 2H) 3.79-3.86 (m, 2H)3.44-3.51 (m, 4H) 3.27-3.32 (m, 4H) 1.43 (s, 9H)

ESI (+) MS m/z 572 (MH⁺)

ESI (+) HRMS calcd for C₃₂N₅O₅H₃₇+H⁺: 572.2868; found 572.2862

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-benzamide(Cpd. 19)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40 (s, 1H) 10.18 (s, 1H) 7.83 (d,J=8.91 Hz, 2H) 7.58 (d, J=8.91 Hz, 1H) 7.34-7.39 (m, 4H) 7.25-7.30 (m,1H) 6.84 (d, J=2.07 Hz, 1H) 6.69 (dd, J=8.91, 2.20 Hz, 1H) 6.62 (d,J=8.91 Hz, 2H) 6.15 (d, J=7.81 Hz, 1H) 4.58 (s, 2H) 4.17-4.23 (m, 2H)3.78-3.84 (m, 2H) 2.70-2.78 (m, 2H) 2.17 (s, 3H) 1.96-2.09 (m, 2H)1.83-1.94 (m, 2H) 1.33-1.51 (m, 2H)

ESI (+) MS m/z 500 (MH⁺)

ESI (+) HRMS calcd for C₂₉N₅O₃H₃₃+H⁺: 500.2656; found 500.2648

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzamide(Cpd. 23)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.42 (s, 1H) 10.28 (s, 1H) 7.93 (d,J=8.91 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.39 (m, 4H) 7.25-7.34 (m,1H) 6.80-6.87 (m, 3H) 6.70 (dd, J=8.91, 2.07 Hz, 1H) 4.58 (s, 2H)4.17-4.23 (m, 2H) 3.79-3.85 (m, 2H) 3.66-3.79 (m, 1H) 2.82-2.88 (m, 2H)2.82 (s, 3H) 2.19 (s, 3H) 2.00-2.11 (m, 2H) 1.71-1.85 (m, 2H) 1.55-1.64(m, 2H)

ESI (+) MS m/z 514 (MH⁺)

ESI (+) HRMS calcd for C₃₀N₅O₃H₃₅+H⁺: 514.2813; found 514.2792

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-morpholin-4-yl-benzamide(Cpd. 24)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.45 (s, 1H) 10.40 (s, 1H) 7.97 (d,J=9.03 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.34-7.39 (m, 4H) 7.25-7.33 (m,1H) 7.02 (d, J=9.03 Hz, 2H) 6.85 (d, J=1.83 Hz, 1H) 6.71 (dd, J=8.91,2.20 Hz, 1H) 4.58 (s, 2H) 4.16-4.23 (m, 2H) 3.78-3.84 (m, 2H) 3.71-3.77(m, 4H) 3.24-3.28 (m, 4H)

ESI (+) MS m/z 473 (MH⁺)

ESI (+) HRMS calcd for C₂₇N₄O₄H₂₈+H⁺: 473.2184; found 473.2169

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(2-morpholin-4-yl-ethylamino)-benzamidehydrochloride (Cpd. 25)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (bs, 1H) 10.66 (bs, 1H) 10.30(s, 1H) 7.91 (d, J=8.79 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.39 (m,4H) 7.25-7.32 (m, 1H) 6.85 (d, J=1.83 Hz, 1H) 6.67-6.75 (m, 3H) 4.58 (s,2H) 4.16-4.23 (m, 2H) 3.90-4.04 (m, 2H) 3.70-3.87 (m, 4H) 3.54-3.62 (m,2H) 3.44-3.54 (m, 2H) 3.24-3.33 (m, 2H) 3.03-3.23 (m, 2H)

ESI (+) MS m/z 516 (MH⁺)

ESI (+) HRMS calcd for C₂₉N₅O₄H₃₃+H⁺: 516.2606; found 516.2584

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(tetrahydro-pyran-4-ylamino)-benzamide(Cpd. 26)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40 (s, 1H) 10.20 (s, 1H) 7.84 (d,J=8.67 Hz, 2H) 7.58 (d, J=8.91 Hz, 1H) 7.34-7.38 (m, 4H) 7.26-7.31 (m,1H) 6.84 (d, J=1.71 Hz, 1H) 6.70 (dd, J=8.91, 1.83 Hz, 1H) 6.65 (d,J=8.67 Hz, 2H) 6.22 (d, J=7.81 Hz, 1H) 4.58 (s, 2H) 4.16-4.22 (m, 2H)3.84-3.92 (m, 2H) 3.79-3.84 (m, 2H) 3.50-3.63 (m, 1H) 3.40-3.48 (m, 2H)1.85-1.94 (m, 2H) 1.32-1.47 (m, 2H)

ESI (+) MS m/z 487 (MH⁺)

ESI (+) HRMS calcd for C₂₈N₄O₄H₃₀+H⁺: 487.2340; found 487.2340

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(1-methyl-piperidin-4-ylmethyl)-amino]-benzamide(Cpd. 27)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39 (s, 1H) 10.18 (s, 1H) 7.83 (d,J=8.67 Hz, 2H) 7.58 (d, J=8.91 Hz, 1H) 7.33-7.40 (m, 4H) 7.25-7.30 (m,1H) 6.84 (d, J=1.83 Hz, 1H) 6.70 (dd, J=8.91, 2.07 Hz, 1H) 6.61 (d,J=8.79 Hz, 2H) 6.33 (t, J=5.68 Hz, 1H) 4.58 (s, 2H) 4.17-4.23 (m, 2H)3.78-3.85 (m, 2H) 2.97 (t, J=6.16 Hz, 2H) 2.72-2.80 (m, 2H) 2.14 (s, 3H)1.76-1.86 (m, 2H) 1.67-1.76 (m, 2H) 1.42-1.59 (m, 1H) 1.14-1.30 (m, 2H)

ESI (+) MS m/z 514 (MH⁺)

ESI (+) HRMS calcd for C₃₀N₅O₃H₃₅+H⁺: 514.2813; found 514.2797

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(3-pyrrolidin-1-yl-azetidin-1-yl)-benzamide(Cpd. 28)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.42 (s, 1H) 10.30 (s, 1H) 7.93 (d,J=8.67 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.32-7.40 (m, 4H) 7.26-7.30 (m,1H) 6.85 (d, J=1.95 Hz, 1H) 6.70 (dd, J=8.91, 2.07 Hz, 1H) 6.45 (d,J=8.79 Hz, 2H) 4.58 (s, 2H) 4.10-4.27 (m, 2H) 4.00 (t, J=7.38 Hz, 2H)3.80-3.87 (m, 2H) 3.75 (dd, J=7.87, 4.94 Hz, 2H) 3.41-3.49 (m, 1H)2.45-2.49 (m, 4H) 1.66-1.82 (m, 4H)

ESI (+) MS m/z 512 (MH⁺)

ESI (+) HRMS calcd for C₃₀N₅O₃H₃₃+H⁺: 512.2656; found 512.2650

EXAMPLE 4N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-4-oxy-piperazin-1-yl)-benzamide(Cpd. 14)

Conversion 7

A solution ofN-[6-(2-benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(300 mg, 0.62 mmol) in DCM (5 ml) and MeOH (5 ml) was treated at r.t.with 3-chloroperbenzoic acid (107 mg, 0.62 mmol). After stirring for 2 hat r.t. the precipitated solid was filtered, washed with few ml ofDCM/MeOH 1:1 and with MeOH and dried in vacuo affording 125 mg of thetitle compound (yield: 40%) as a white solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d6): 12.47 (s, 1H) 10.43 (s, 1H)7.95-8.02 (m, 2H) 7.60 (d, J=9.08 Hz, 1H) 7.25-7.40 (m, 5H) 7.03-7.12(m, 2H) 6.86 (d, J=2.05 Hz, 1H) 6.71 (dd, J=9.08, 2.05 Hz, 1H) 4.59 (s,2H) 4.16-4.24 (m, 2H) 3.79-3.86 (m, 2H) 3.67-3.77 (m, 2H) 3.43-3.63 (m,4H) 3.12 (s, 3H) 3.96-3.07 (m, 2H)

ESI (+) MS m/z 502 (MH⁺)

ESI (+) HRMS calcd for C₂₈N₅O₄H₃₁+H⁺: 502.2449; found 502.2443

The title compound (120 mg) was then suspended in 10 ml of ethanol,treated with 2N HCl (0.5 ml) and stirred until a clear solution wasobtained. Evaporation of the solvent, trituration with diethyl ether anddrying in vacuo afforded 127 mg of the hydrochloride salt of the titlecompound as a white solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.55 (s, 1H) 12.51 (bs, 1H) 10.48(s, 1H) 8.02 (d, J=8.79 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.41 (m,4H) 7.25-7.32 (m, 1H) 7.13 (d, J=8.91 Hz, 2H) 6.86 (d, J=1.59 Hz, 1H)6.72 (dd, J=8.85, 1.89 Hz, 1H) 4.58 (s, 2H) 4.14-4.26 (m, 2H) 3.94-4.03(m, 2H) 3.74-3.89 (m, 6H) 3.59 (s, 3H) 3.40-3.50 (m, 2H)

ESI (+) MS m/z 502 (MH⁺)

ESI (+) HRMS calcd for C₂₈N₅O₄H₃₁+H⁺: 502.2449; found 502.2438

Operating in an analogous way, the following compounds were obtained:

N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-1-oxy-piperidin-4-yl)-amino]-benzamide(Cpd. 41)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.49 (s, 1H) 10.32 (s, 1H) 7.95 (d,J=9.03 Hz, 2H) 7.59 (d, J=8.91 Hz, 1H) 7.33-7.41 (m, 4H) 7.24-7.33 (m,1H) 6.87 (d, J=9.15 Hz, 2H) 6.85 (d, J=2.20 Hz, 1H) 6.70 (dd, J=8.97,2.14 Hz, 1H) 4.58 (s, 2H) 4.15-4.24 (m, 2H) 3.93-4.06 (m, 1H) 3.77-3.85(m, 2H) 3.45-3.56 (m, 2H) 3.07 (s, 3H) 3.03 (br. s., 1H) 2.86 (s, 3H)2.43-2.55 (m, 3H) 1.48 (m, J=12.08 Hz, 2H)

ESI (+) MS m/z 530 (MH⁺)

ESI (+) HRMS calcd for C₃₀H₃₅N₅O₄+H⁺: 530.2762; found 530.2769

4-(4-Methyl-4-oxy-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamidehydrochloride (Cpd. 42)

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.55 (s, 1H) 12.50 (br. s., 1H)10.49 (s, 1H) 8.03 (d, J=8.97 Hz, 2H) 7.72 (d, J=8.06 Hz, 2H) 7.57-7.61(m, 3H) 7.10-7.15 (m, 2H) 6.87 (d, J=1.83 Hz, 1H) 6.73 (dd, J=8.88, 2.11Hz, 1H) 4.70 (s, 2H) 4.21-4.25 (m, 2H) 3.99 (d, J=14.29 Hz, 2H)3.75-3.89 (m, 6H) 3.59 (s, 3H) 3.40-3.48 (m, 2H)

ESI (+) MS m/z 570 (MH⁺)

ESI (+) HRMS calcd for C₂₉H₃₀F₃N₅O₄+H⁺: 570.2323; found 570.2330

EXAMPLE 5N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-piperazin-1-yl-benzamide(Cpd. 20)

Conversion 8

A solution of4-{4-[6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylcarbamoyl]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (180 mg, 0.31 mmol) in 1,4-dioxane (10 ml) andMeOH (5 ml) was treated with 4M hydrochloric acid in 1,4-dioxane (6 ml,24 mmol). After stirring for 2 h at r.t. the reaction mixture wasevaporated to dryness, diluted with water (50 ml) and brought to basicpH by addition of a saturated solution of NaHCO₃. The precipitated solidwas filtered, washed with water, dried and purified by chromatography(Biotage SP1 Flash Purification system) on a silica gel cartridge(Biotage SNAP 25 g) using DCM as eluant A and DCM/7N NH₃ in MeOH 10:1 aseluant B. Elution with a gradient from A/B 100:0 to 0:100 over 15 CV,followed by an isocratic elution with eluant B (5 CV), gave a yellowsolid that was triturated with diethyl ether (15 ml) affording 111 mg(yield: 75%) of the title compound as a white solid.

¹H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44 (s, 1H) 10.36 (s, 1H) 7.95 (d,J=9.03 Hz, 2H) 7.59 (d, J=9.03 Hz, 1H) 7.33-7.40 (m, 4H) 7.25-7.32 (m,1H) 6.98 (d, J=9.15 Hz, 2H) 6.85 (d, J=1.95 Hz, 1H) 6.71 (dd, J=2.07,8.91 Hz, 1H) 4.58 (s, 2H) 4.15-4.25 (m, 2H) 3.77-3.86 (m, 2H) 3.17-3.23(m, 4H) 2.78-2.86 (m, 4H)

ESI (+) MS m/z 472 (MH⁺)

ESI (+) HRMS calcd for C₂₇N₅O₃H₂₉+H⁺: 472.2343; found 472.2327

Pharmacology

The short forms and abbreviations used herein have the followingmeaning:

DMSO dimethylsulfoxide

g gram

IC₅₀ concentration inhibiting by 50%

mg milligram

microg microgram

microL microliter

mL milliliter

mM millimolar

microM micromolar

nM nanomolar

Assays

Compounds of the present invention were tested in biochemical assays, asdescribed below.

Preparation of FLT3 and KIT Kinase Cytoplasmic Domains for use inBiochemical Assay

Cloning, Expression and Purification

FLT3 cytoplasmic domain (aa 564-993end of the 993 aminoacid long fulllength sequence, accession number P36888 of UniProtKB/Swiss-Prot.database) was amplified by PCR starting from a testis cDNA library andthen cloned into pVL vector for expression in insect cells through thebaculovirus system. The GST-FLT3 cytoplasmic domain has been expressedin Sf21 cells infected for 72 hours at 27° C. The recombinant proteinhas been purified by affinity on GSH-sepharose and eluted withglutathione. A further purification step has been performed on heparinesepharose. The final yield was of 0.5 mg/billion cells and the proteinresulted >90% pure by coomassie staining.

KIT cytoplasmic domain (aa 544-976end of the 976 aminoacid long fulllength sequence, accession number P10721 of UniProtKB/Swiss-Protdatabase) was cloned into pVL vector for expression in insect cellsthrough the baculovirus system. The GST-KIT cytoplasmic domain has beenexpressed in Sf21 cells infected for 66 hrs at 27° C. The recombinantprotein has been purified by affinity on GSH-sepharose and eluted withglutathione. The final yield was of 9 mg/billion cells and the proteinresulted >80% pure by coomassie staining.

Purified proteins were stored at −80° C. prior its use in biochemicalassay.

Biochemical Assays

i. General Principle—A specific peptidic substrate wastrans-phosphorylated by the kinase in the presence of ATP traced with33Pγ-ATP. At the end of the phosphorylation reaction, the not reactedATP, cold and radioactive, was captured by an excess of dowex ionexchange resin that eventually settled by gravity to the bottom of thereaction plate. The supernatant was subsequently withdrawn andtransferred into a counting plate that was then evaluated by β-counting.

ii. Dowex resin preparation—500 g of wet resin (SIGMA, custom preparedresin DOWEX 1×8 200-400 mesh, 2.5 Kg) were weighed out and diluted to 2L in 150 mM sodium formate, pH 3.00. The resin was allowed to settledown overnight and then the supernatant was discarded. After threewashes as above over a couple of days, the resin was allowed to settleand two volumes (with respect to the resin volume) were added of 150 mMsodium formate buffer.

Biochemical Assay for Inhibitors of FLT3 Kinase Activity

i. Enzyme—The assay was performed using FLT3 cytoplasmic domain productand purified in house as GST fused protein. The FLT3 protein (1 microM)was pre activated with 800 microM ATP for 1 hour at 28*C in order toobtain a linear kinetic.

ii. FLT3 Kinase Buffer (KB)—Kinase buffer was composed of 50 mM HEPES pH7.9 containing 4 mM MgCl₂, 1 mM DTT, 10 microM Na₃VO₄, and 0.2 mg/mL BSA

iii. Assay conditions—The FLT3 kinase assay was run with a final preactivated enzyme concentration of 2 nM, in the presence of 254 microMATP (residual ATP from KIT pre activation step is negligible), 8 nM33P-γ-ATP and 55 microM of substrate BioDB n*24 (Aminoacidic sequence:GGKKKVSRSGLYRSPSMPENLNRPR- SEQ ID NO: 1). The peptide was purchased fromAmerican Peptide Company (Sunnyvale, Calif.).

Biochemical Assay for Inhibitors of KIT Kinase Activity

i. Enzyme—The assay has been performed using KIT cytoplasmic domainproduct and purified in house as GST fused protein. The KIT protein (4.5microM) was pre activated with 300 microM ATP for 1 hour at 28*C inorder to obtain a linear kinetic.

ii. KIT kinase Buffer (KB)—Kinase buffer was composed of 50 mM HEPES pH7.9 containing 5 mM MgCl₂, 1 mM MnCl₂, 10 mM DTT, 3 microM Na₃VO₄, and0.2 mg/mL BSA

iii. Assay conditions—The KIT kinase assay was run with a final preactivated enzyme concentration of 4 nM, in the presence of 4.4 microMATP (residual ATP from KIT pre activation step is negligible), 3.9 nM33P-γ-ATP and 2.5 microM of substrate BioDB n*138 (Aminoacidic sequence:KWEEINGNNYVYIDPTQLPYDHKWEFPRNR- SEQ ID NO: 2). The peptide was purchasedfrom American Peptide Company (Sunnyvale, Calif.).

Compound Testing

i. Compound Dilution—For IC₅₀ determination, test compounds werereceived as a 1 mM solution in 100% DMSO, distributed into 96 wellplates: compounds were then plated into the first column of a microtiterplate (A1 to G1), 100 microL/well. An automated station for serialdilutions (Biomek FX, Beckman) was used for producing 1:3 dilutions in100% DMSO, from line A1 to A10, and for all the compounds in the column.Moreover, 4-5 copies of daughter plates were prepared by reformatting 5microL of this first set of 100% DMSO dilution plates into 384 deepwell-plates: one of these plates with the serial dilutions of testcompounds was thawed the day of the experiments, reconstituted at a 3×concentration with water and used in the IC₅₀ determination assays. In astandard experiment, the highest concentration (3×) of all compounds was30 microM, while the lowest one was 1.5 nM.

Each 384 well-plate contained at least one curve of the standardinhibitor staurosporine and reference wells (total enzyme activity vs.no enzymatic activity) for the Z′ and signal to background evaluation.

ii. Assay Scheme—384-well plates, V bottom (test plates) were preparedwith 5 microL of the compound dilution (3×) and then placed onto aPlateTrak 12 robotized station (Perkin Elmer; the robot had one 384-tippipetting head for starting the assay plus one 96-tip head fordispensing the resin) together with one reservoir for the Enzyme mix(3×) and one for the ATP mix (3×). At the start of the run, the robotaspirated 5 μl of ATP mix, made an air gap inside the tips (3 microL)and aspirated 5 microL of Enzyme mix. The following dispensation intothe plates plus 3 cycles of mixing, done by the robot itself, startedthe kinase reaction. At this point, the correct concentrations wererestored for all the reagents. The robot incubated the plates for 60minutes at r.t., and then stopped the reaction by pipetting 60 microL ofdowex resin suspension into the reaction mix. In order to avoid tipclogging, wide bore tips were used to dispense the resin suspension.Three cycles of mixing were done immediately after the addition of theresin. Another mixing cycle was performed after all the plates werestopped, this time using normal tips: the plates were then allowed torest for about one hour in order to allow resin sedimentation. At thispoint, 27 microL of the supernatant were transferred into 384-Optiplates(Perkin-Elmer), with 50 microL of Microscint 40 (Perkin-Elmer); after 5min of orbital shaking the plates were read on a Perkin-Elmer Top Countradioactivity counter.

iii. Data Fitting—Data were analyzed by an internally customized versionof the SW package “Assay Explorer” that provided sigmoidal fitting ofthe ten-dilutions curves for IC₅₀ determination in the secondaryassays/hit confirmation routines.

Cell-Based Assays for Inhibitors of FLT3 Kinase Activity

In Vitro Cell Proliferation Assay for Inhibitors of FLT3 Kinase Activity

The human acute leukemia MOLM-13 AND MV-4-11 cells, bearing a FLT3-ITDmutation, were seeded (5000 cells/well) in white 384 well-plates incomplete medium (RPMI 1640 plus 10% Fetal bovine serum) and treated withcompounds dissolved in 0.1% DMSO, 24 h after seeding. The cells wereincubated at 37° C. and 5% CO₂ and after 72 h the plates were processedusing CellTiter-Glo assay (Promega) following the manufacturer'sinstruction.

CellTiter-Glo is a homogenous method based on the quantification of theATP present, an indicator of metabolitically active cells. ATP wasquantified using a system based on luciferase and D-luciferin resultantinto light generation. The luminescent signal was proportional to thenumber of cells present in culture.

Briefly, 25 microL/well reagent solution were added to each well and,after 5 minutes shaking, microplates were read by Envision (PerkinElmer)luminometer. Inhibitory activity was evaluated comparing treated versuscontrol data using Symyx Assay Explorer (Symyx Technologies Inc.)program. IC₅₀ was calculated using sigmoidal interpolation curve. Thecompounds of formula (I) tested as described above, resulted to possessa remarkable FLT3 and KIT inhibitory activity, together with very goodpotency in inhibiting MOLM-13 AND MV-4-11 cells proliferation.

See, as an example, the following Table I, reporting the experimentaldata of some representative compounds of the invention being tested inbiochemical assays as FLT3 and KIT kinase inhibitors (IC₅₀ microM), andTable II, reporting the experimental data of some representativecompounds of the invention being tested in cell proliferation assays asMOLM-13 and MV-4-11 inhibitors (IC₅₀ microM), in comparison with theclosest compound of the prior art (Ref. compound), described inWO03/028720, page 77, Table XI, entry 226, compound A02-M2-B05, havingthe following structure:

In biochemical assays, the IC₅₀ values are typically lower than 2 microMon FLT3 and lower than 3 microM on KIT. In cell proliferation assays,the IC₅₀ values are typically lower than 3 microM, with 26 compoundshaving IC₅₀ values lower than 0.1 microM on both cell lines.

TABLE I FLT3 IC₅₀ (microM) KIT IC₅₀ (microM) Cpd No. Biochemical assayBiochemical assay  1 0.428 2.805  2 1.134 0.172  3 0.639 0.564  40.974 >10  5 1.171 2.619  6 0.248 6.888  7 0.249 1.505  9 1.504 0.713 10<0.050 0.956 11 <0.050 0.113 14 <0.050 0.118 15 <0.050 0.076 16 <0.0500.106 17 0.062 0.146 18 0.414 1.392 19 <0.050 0.061 20 <0.050 0.052 210.104 0.134 22 0.056 0.055 23 <0.050 0.109 24 0.162 0.260 25 0.074 0.19726 0.090 0.124 27 <0.050 0.091 28 0.136 0.306 29 0.635 1.078 30 0.1661.405 32 <0.050 <0.050 33 <0.050 <0.050 34 0.056 0.058 35 1.176 2.370 380.539 0.613 39 0.062 0.528 40 <0.050 0.088 41 0.052 0.180 42 <0.0500.055 Ref. Compound 3.175 >10

TABLE II MOLM-13 IC₅₀ (microM) MV-4-11 IC₅₀ (microM) Cpd No. Cellproliferation assay Cell proliferation assay  1 0.789 0.683  2 1.1581.475  3 0.990 0.987  4 0.092 <0.050  5 0.557 0.513  6 0.673 0.163  70.240 0.110  8 1.978 2.753  9 0.245 0.101 10 0.139 0.118 11 <0.050<0.050 14 <0.050 <0.050 15 <0.050 <0.050 16 <0.050 <0.050 17 0.087<0.050 19 <0.050 <0.050 20 <0.050 <0.050 21 0.068 <0.050 22 0.065 <0.05023 <0.050 <0.050 24 <0.050 <0.050 25 <0.050 <0.050 26 <0.050 <0.050 27<0.050 <0.050 28 <0.050 <0.050 29 <0.050 <0.050 30 <0.050 <0.050 32<0.050 <0.050 33 <0.050 <0.050 34 <0.050 <0.050 35 <0.050 <0.050 38<0.050 <0.050 39 0.081 0.050 40 <0.050 <0.050 41 <0.050 <0.050 43 0.2400.118 Ref. Compound 3.911 5.537

1. A compound of formula (I):

wherein: Ar is a group selected from

wherein: R1 is A, NR6R7, OR8, SO_(n)R9, COR10, nitro, cyano or anoptionally substituted group selected from C₃-C₆ cycloalkyl,heterocyclyl and heteroaryl; R2, R3, R4 and R5 are independentlyhydrogen, halogen, nitro, cyano, SO_(n)R9, COR10, NR11R12, OR13 or anoptionally substituted group selected from straight or branched C₁-C₆alkyl, straight or branched C₂-C₆ alkenyl, straight or branched C₂-C₆alkynyl, C₃-C₆ cycloalkyl and heterocyclyl wherein: A is a straight orbranched C₁-C₆ alkyl substituted with a group selected from anoptionally substituted heterocyclyl, an optionally substitutedheteroaryl, SO_(n)R9, COR10, NR11R12 and OR13; R6 is hydrogen or anoptionally substituted group selected from straight or branched C₁-C₆alkyl, straight or branched C₂-C₆ alkenyl, straight or branched C₂-C₆alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl and heteroaryl; R7 ishydrogen, SO_(n)R9, COR10, a substituted straight or branched C₁-C₆alkyl or an optionally substituted group selected from straight orbranched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆cycloalkyl, heterocyclyl, aryl and heteroaryl or R6 and R7, takentogether with the nitrogen atom to which they are bound, may form anoptionally substituted heterocyclyl group; R8 is hydrogen, A, COR10 oran optionally substituted group selected from straight or branched C₂-C₆alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,heterocyclyl, aryl and heteroaryl, wherein A is as defined above; R9 isNR11R12 or an optionally substituted group selected from straight orbranched C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight orbranched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl andheteroaryl; R10 is hydrogen, NR11R12, OR13 or an optionally substitutedgroup selected from straight or branched C₁-C₆ alkyl, straight orbranched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆cycloalkyl, heterocyclyl, aryl and heteroaryl; R11 and R12 areindependently hydrogen, SO_(n)R9, COR10 or an optionally substitutedgroup selected from straight or branched C₁-C₆ alkyl, straight orbranched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R9 and R10 are asdefined above, or R11 and R12, taken together with the nitrogen atom towhich they are bound, may form an optionally substituted heterocyclylgroup; R13 is hydrogen, COR10 or an optionally substituted groupselected from straight or branched C₁-C₆ alkyl, straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,heterocyclyl, aryl and heteroaryl, wherein R10 is as defined above; n is0,1 or 2; X is a bond or an optionally substituted group selected fromstraight or branched C₁-C₆ alkyl, heterocycly and aryl; Y is a bond,oxygen, or an optionally substituted group selected from straight orbranched C₁-C₆ alkyl, straight or branched C₂-C₆ alkenyl, straight orbranched C₂-C₆ alkynyl, heterocyclyl and aryl; Z is a bond, oxygen or anoptionally substituted straight or branched C₁-C₆ alkyl; Ar′ is anoptionally substituted aryl or an optionally substituted heteroaryl; ora pharmaceutically acceptable salt thereof.
 2. The compound of formula(I) as defined in claim 1 wherein: R1 is A, NR6R7, OR8 or an optionallysubstituted heterocyclyl, wherein A, R6, R7 and R8 are as defined inclaim
 1. 3. The compound of formula (I) as defined in claim 1 wherein:Ar is Ar1 or Ar2; and R2, R3, R4, R5 are each independently hydrogen,halogen, NR11R12 or OR13, wherein R11, R12 and R13 are as defined inclaim
 1. 4. A compound of formula (I) or a pharmaceutically acceptablesalt thereof as defined in claim 1 which is selected from the groupconsisting of:N-(6-Benzyloxy-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide,4-(4-Methyl-piperazin-1-yl)-N-(6-phenoxy-1H-indazol-3-yl)-benzamide,N-[6-(3-Fluoro-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,N-[6-(4-Benzyloxy-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,4-(4-Methyl-piperazin-1-yl)-N-[6-(3-phenoxy-benzyloxy)-1H-indazol-3-yl]-benzamide,N-[6-(1-Benzyl-piperidin-4-yloxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,4-(4-Methyl-piperazin-1-yl)-N-[6-(3-phenyl-prop-2-ynyloxy)-1H-indazol-3-yl]-benzamide,4-(4-Methyl-piperazin-1-yl)-N-[6-(4-phenoxy-phenoxy)-1H-indazol-3-yl]-benzamide,N-[6-(3-Benzyloxy-phenoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,4-(4-Methyl-piperazin-1-yl)-N-[6-(2-phenoxy-ethoxy)-1H-indazol-3-yl]-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,N-[6-(1-Benzyl-piperidin-3-yloxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,N-[6-(1-Benzyl-pyrrolidin-2-ylmethoxy)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-methyl-4-oxy-piperazin-1-yl)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(4-dimethylamino-piperidin-1-yl)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide,4-{4-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-ylcarbamoyl]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-ylamino)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-piperazin-1-yl-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-dimethylaminomethyl-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-piperidin-4-yl)-amino]-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-morpholin-4-yl-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(2-morpholin-4-yl-ethylamino)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(tetrahydro-pyran-4-ylamino)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[(1-methyl-piperidin-4-ylmethyl)-amino]-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-(3-pyrrolidin-1-yl-azetidin-1-yl)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-3-(4-methyl-piperazin-1-yl)-benzamide,N-{6-[2-(2-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,N-{6-[2-(3-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,N-{6-[2-(4-Fluoro-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide,4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(3-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamide,4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(pyridin-4-ylmethoxy)-ethoxy]-1H-indazol-3-yl}-benzamide,4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(pyridin-3-ylmethoxy)-ethoxy]-1H-indazol-3-yl}-benzamide,4-(4-Methyl-piperazin-1-yl)-N-{6-[2-(pyridin-2-ylmethoxy)-ethoxy]-1H-indazol-3-yl}-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-2-fluoro-4-(4-methyl-piperazin-1-yl)-benzamide,4-(4-Methyl-piperazin-1-yl)-N-[6-((E)-3-phenyl-allyloxy)-1H-indazol-3-yl]-benzamide,N-{6-[2-(4-Methoxy-benzyloxy)-ethoxy]-1H-indazol-3-yl}-4-(4-methyl-piperazin-1-yl)-benzamide,N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-4-[methyl-(1-methyl-1-oxy-piperidin-4-yl)-amino]-benzamide,4-(4-Methyl-4-oxy-piperazin-1-yl)-N-{6-[2-(4-trifluoromethyl-benzyloxy)-ethoxy]-1H-indazol-3-yl}-benzamideandN-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl]-2,4-bis-(4-methyl-piperazin-1-yl)-benzamide.5. A process for preparing a compound of formula (I) as defined in claim1 or a pharmaceutically acceptable salt thereof, characterized in thatthe process comprises the following steps: F) cleaving thetert-butoxy-carbonyl group of the compound of formula (XI)

wherein Ar, Ar′, X, Y and Z are as defined in claim 1, so as to obtain acompound of formula (I), as defined above; or in alternative L)acylating the compound of formula (XVI)

wherein Ar′, X, Y and Z are as defined in claim 1, with a compound offormula (V)

wherein Ar is as defined in claim 1 and W is hydroxy, halogen or asuitable leaving group; so as to obtain a compound of formula (I), asdefined above; or in alternative M) acylating the compound of formula(XVI), as defined above, with a compound of formula (XVII)

wherein R2, R3, R4 and R5 are as defined in claim 1, W is as definedabove and L is a suitable leaving group, such as halogen,methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy;N) coupling the resultant compound of formula (XVIII)

wherein Ar′, X, Y, Z, R2, R3, R4 and R5 are as defined in claim 1 and Lis as defined above, with a compound of formula (XIX)

wherein R6 is as defined in claims 1 and R7 is hydrogen, a substitutedstraight or branched C₁-C₆ alkyl or an optionally substituted groupselected from straight or branched C₂-C₆ alkenyl, straight or branchedC₂-C₆ alkynyl, C₃-C₆ cycloalkyl, heterocyclyl, aryl and heteroaryl, soas to obtain a compound of formula (I), wherein R1 is NR6R7, wherein R6is as defined in formula (I) and R7 is hydrogen, a substituted straightor branched C₁-C₆ alkyl or an optionally substituted group selected fromstraight or branched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, heterocyclyl, aryl and heteroaryl, and Ar, Ar′, X, Y,Z are as defined in claim 1; optionally separating the resultantcompound of formula (I) into the single isomers; optionally convertingthe resultant compound of formula (I) into a different compound offormula (I), and/or into a pharmaceutically acceptable salt.
 6. Theprocess according to claim 5, characterized in that the compound offormula (XI) as defined in claim 5 is prepared according to thefollowing steps: A) introducing the tert-butoxy-carbonyl group into thecompound of formula (II)

B) cleaving the phthalimido group of the resultant compound of formula(III)

C) acylating the resultant compound of formula (IV)

by reaction with a compound of formula (V)

wherein Ar is as defined in claim 5 and W is hydroxy, halogen or asuitable leaving group; D) selectively cleaving thetert-butyldimethylsilyl ether of the resultant compound of formula (VI)

wherein Ar is as defined above; E) coupling the resultant compound offormula (VII)

wherein Ar is as defined above, alternatively with: Ea) a compound offormula (VIII)

wherein Ar′, Z and Y are as defined in claim 5 and X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl andheterocyclyl; or Eb) a compound of formula (IX)

wherein Ar′, Z and Y are as defined in claim 5 and X is an optionallysubstituted aryl or wherein Ar′ is as defined in claim 5 and X, Y and Zare a bond; or Ec) a compound of formula (X)

wherein Ar′, Z and Y are as defined in claim 5, X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl orheterocyclyl and L is a suitable leaving group such as halogen,methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy;so as to obtain a compound of formula (XI), as defined in claim
 5. 7.The process according to claim 5, characterized in that the compound offormula (XI) as defined in claim 5 is prepared according to thefollowing steps: G) selectively cleaving a tert-butyldimethylsilyl etherof the compound of formula (IV),

H) coupling the resultant compound of formula (XII)

alternatively with: Ha) a compound of formula (VIII),

wherein Ar′, Z and Y are as defined in claim 5 and X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl andheterocyclyl; or Hb) a compound of formula (X),

wherein Ar′, Z and Y are as defined in claim 5, X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl orheterocyclyl and L is a suitable leaving group such as halogen,methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy;I) acylating the resultant compound of formula (XIII)

wherein Ar, Ar′, Y and Z are as defined in claim 5 and X is anoptionally substituted group selected from straight or branched C₁-C₆alkyl and heterocyclyl, with a compound of formula (V),

wherein Ar is as defined in claim 5 and W is hydroxy, halogen or asuitable leaving group; so as to obtain a compound of formula (XI),wherein Ar, Ar′, Y and Z are as defined in claim 5 and X is anoptionally substituted group selected from straight or branched C₁-C₆alkyl and heterocyclyl.
 8. The process according to claim 5,characterized in that the compound of formula (XVI) as defined in claim5 is prepared according to the following steps: J) coupling the compoundof formula (XIV)

alternatively with: Ja) a compound of formula (VIII),

wherein Ar′, Z and Y are as defined in claim 5 and X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl andheterocyclyl; or Jb) a compound of formula (IX),

wherein Ar′, Z and Y are as defined in claim 5 and X is an optionallysubstituted aryl or wherein Ar′ is as defined in claim 5 and X, Y and Zare a bond; or Jc) a compound of formula (X),

wherein Ar′, Z and Y are as defined in claim 5, X is an optionallysubstituted group selected from straight or branched C₁-C₆ alkyl orheterocyclyl and L is a suitable leaving group such as halogen,methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.K) converting the resultant compound of formula (XV)

wherein Ar′, X, Y and Z are as defined in claim 5 so as to obtain acompound of formula (XVI), as defined in claim
 5. 9. A method oftreating a disease caused by and/or associated with a degulated proteinkinase activity which comprises administering to a mammal in needthereof an effective amount of a compound of formula (I) as defined inclaim
 1. 10. The method according to claim 9 wherein the mammal in needthereof is a human.
 11. The method according to claim 9 of treating adisease caused by and/or associated with a degulated FLT3 or KIT kinaseactivity.
 12. The method according to claim 9 wherein the disease isselected from the group consisting of cancer, cell proliferationdisorders and immune cell-associated diseases and disorders.
 13. Themethod according to claim 12 wherein the cancer is selected from thegroup consisting of carcinoma such as bladder, breast, colon, kidney,liver, lung, including small cell lung cancer, salivary gland,esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid,thymus, prostate, and skin, including squamous cell carcinoma;hematopoietic tumors of lymphoid lineage including leukemia, acutelymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma and Burkitt's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukemia; tumors ofmesenchymal origin, including gastrointestinal stromal tumor,fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheralnervous system, including astrocytoma neuroblastoma, glioma andschwannomas; other tumors, including mast cell disease, melanoma,seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum,keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma andmesothelioma and others.
 14. The method according to claim 12 whereinthe cellular proliferation disorder is selected from the groupconsisting of benign prostate hyperplasia, familial adenomatosispolyposis, neurofibromatosis, psoriasis, vascular smooth cellproliferation associated with atherosclerosis, pulmonary fibrosis,arthritis, glomerulonephritis and post-surgical stenosis and restenosis.15. The method according to claim 12 wherein the immune cell-associateddisease or disorder is selected from the group consisting ofinflammatory and autoimmune diseases, multiple sclerosis, systemic lupuserythematosis, inflammatory bowel diseases (IBD), Crohn's disease,irritable bowel syndrome, pancreatitis, ulcerative colitis,diverticulosis, myasthenia gravis, vasculitis, psoriasis, scleroderma,asthma, allergy, systemic sclerosis, vitiligo, arthritis,osteoarthritis, juvenile rheumatoid arthritis and ankylosingspondylitis.
 16. The method according to claim 13 wherein the cancer isa FLT3 mutated cancer.
 17. The method according to claim 13 wherein thecancer is a KIT mutated cancer.
 18. The method according to claim 9which provides tumor angiogenesis and metastasis inhibition.
 19. Themethod according to claim 13 further comprising subjecting the mammal inneed thereof to a radiation therapy or chemotherapy regimen incombination with at least one cytostatic or cytotoxic agent.
 20. An invitro method for inhibiting FLT3 or KIT protein kinase activity whichcomprises contacting the said protein with an effective amount of acompound of formula (I) as defined in claim
 1. 21. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, as definedin claim 1, and at least one pharmaceutically acceptable excipient,carrier and/or diluent.
 22. A pharmaceutical composition according toclaim 21 further comprising one or more chemotherapeutic agents.
 23. Aproduct comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, as defined in claim 1, and one or morechemotherapeutic agents, as a combined preparation for simultaneous,separate or sequential use in anticancer therapy. 24.-26. (canceled) 27.The method according to claim 16 wherein the FLT3 mutated cancer isacute myeloid leukaemia or myelodisplastic syndrome.
 28. The methodaccording to claim 17 wherein the KIT mutated cancer is gastrointestinalstromal tumors, melanoma, acute myeloid leukemia, primary adenoid cysticcarcinoma of the salivary gland, thymic carcinoma, glioma, testicularseminoma, small cell lung cancers, mast cell disease or piebaldism.